A prospective study of investigating the efficacy of FOLFIRI plus Aflibercept as a 2nd line therapy after progression during FOLFOXIRI plus Bevacizumab in unrescetable / metastatic colorectal cancer (CRC) patients.

JRCT ID: jRCTs071190003

Registered date:18/04/2019

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: Colorectal Cancer
• Date of first enrollment: 13/06/2019
• Target sample size: 35
• Study type: Interventional
• Intervention(s): Patients receive aflibercept (4 mg/kg) every 2 weeks on day 1 of each cycle followed immediately by FOLFIRI. Treatment continues until disease progression, unacceptable toxicity, death, patient refusal, or investigator decision.

Outcome(s)

• Primary Outcome: Progression free survival

Secondary Outcome

Response Rate
Overall survival

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1)Written informed consent obtained from every patient before enrollment in the study.
2)The lead investigator deems that the patient can be treated according to the protocol (the patient is suitable for enrollment).
3)Patients with histologically confirmed advanced unresectable colorectal cancer (CRC) or metastatic CRC (mCRC).
4)RAS mutation status should be known. If possible BRAF mutation status as well.
5)Patients with unresectable CRC or mCRC who received FOLFOXIRI+bevacizumab as a first-line therapy. The reason for discontinuation of first line therapy is progressive disease (PD).
Patients with unresectable CRC or mCRC who discontinued first-line therapy with FOLFOXIRI+bevacizumab.
Patients who underwent adjuvant chemotherapy and FOLFOXIRI+bevacizumab treatment following recurrence. The date of recurrence confirmation should be at least 6 months from the final day of adjuvant therapy.
Patients who discontinued 5-FU/LV+bevacizumab as a maintenance therapy. FOLFOXIRI+bevacizumab as induction therapy will be administered for no more than 12 cycles.
Patients who underwent both induction therapy (FOLFOXIRI+bevaczizumab) and maintenance therapy (5-FU/LV+bevacizumab) are preferable to this study.
6)Radiation therapy was not administered to the target lesion.
Patients who have received neoadjuvant or adjuvant radiation therapy will be included.
Patients who have received radiation therapy against non-target lesions will be included.
7)Aged >=20 years
8)Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
Patients with unresectable CRC or mCRC who discontinued first-line therapy with FOLFOXIRI+bevacizumab.
Patients who underwent adjuvant chemotherapy and FOLFOXIRI+bevacizumab treatment following recurrence. The date of recurrence confirmation should be at least 6 months from the final day of adjuvant therapy.
Patients who discontinued 5-FU/LV+bevacizumab as a maintenance therapy. FOLFOXIRI+bevacizumab as induction therapy will be administered for no more than 12 cycles.
Patients who underwent both induction therapy (FOLFOXIRI+bevaczizumab) and maintenance therapy (5-FU/LV+bevacizumab) are preferable to this study.
6)Radiation therapy was not administered to the target lesion.
Patients who have received neoadjuvant or adjuvant radiation therapy will be included.
Patients who have received radiation therapy against non-target lesions will be included.
7)Aged >=20 years
8)Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
9)Measurable lesions based on the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.1. Imaging should be performed within 28 days prior to enrolment
Measurable lesions should be 10 mm or more on the major axis using a CT scan with a 5 mm slice. For metastatic lymph nodes, the minor axis should exceed 15 mm in length.
10)Patient who have enough oral ingestion.
11)Patients must have no severe dysfunction of major organs.
WBC>=3,000 cells/mm^3, =<12,000/mm^3
Neutrophil count>=1,500 cells/mm^3
Platelet count>=75,000 cells/mm^3
Hemoglobin>=9.0 g/dL
Total bilirubin<=1.5 mg/dL
AST (GOT)<=100 IU/L or <=200 IU/L in patients with liver metastases
ALT (GPT)<=100 IU/L or <=200 IU/L in patients with liver metastases
Creatinine <1.5 mg/dL
Creatinine clearance (CCr)>=50 mL/min
Protein urea Grade <=1(1+ or <1.0 g/24 h)
UGT1A1 wild-type or UGT1A1*6, or UGT1A1*28 polymorphisms
12)Life expectancy>= 3 months

Exclude criteria

1)Patients with hypertension (>160 mmHg systolic or > 100 mmHg diastolic for >4 weeks) that cannot be adequately controlled with 2 antihypertensive agents*.
*One antihypertensive treatment containing two antihypertensive agents counts as two antihypertensives.
Patients with diabetes mellitus that cannot be adequately controlled with medication.
Patients with heart disease that may cause problems, such as congestive heart failure, angina pectoris requiring medication, clear evidence of transmural myocardial infarction on an ECG, clinically evident valvular heart disease, symptomatic coronary disease, poorly controlled arrhythmia, and a previous history of myocardial infarction within the last 12 months..
2)Patients with severe pulmonary disease, including interstitial pneumonia, pulmonary fibrosis and severe emphysema.
3)Patients with an active infection.
4)Patients with clinically significant ascites and pleural effusion.
5)Patients who have severe drug hypersensitivity (particularly to 5-FU, irinotecan, or aflibercept).
6)Patients with active multiple cancers. Synchronous double cancer and metachronous double cancer within a disease-free interval of 5 years. Lesions consistent with carcinoma in situ or intramucosal carcinoma that have been cured by local treatment are not classified as active multiple cancers.
7)Patients with a psychiatric disorder that may pose a problem, or a history of central nervous system dysfunction.
8)Patients who have brain metastases, or where brain metastases are possible.
9)Patients who have had a gastrointestinal perforation and/or a gastrointestinal fistula up to 6 months prior to enrollment.
10)Watery diarrhea or diarrhea Grade >=2
11)Patients who have had deep vein thrombosis, pulmonary embolism, or some other major form of thromboembolism (portal vein or catheter thrombosis and superficial venous thrombosis qualify as major forms) up to 3 months prior to enrollment.
12)The patient has experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to the first dose of protocol therapy.
13)Daily treatment with high-dose aspirin (>=325 mg/day).
14)Non-steroidal anti-inflammatory medications and immune suppressive or steroidal medications.
15)Patients receiving phenytoin, warfarin potassium, or flucytosine.
16)Women who are pregnant, breast feeding, or who wish to conceive.
17)Men who wish to conceive.
18)Patients with active gastrointestinal tract bleeding requiring repeated transfusions.
19)Patient who underwent resection after FOLFOXIRI+bevacizumab because of conversion and had progressed.
20)Patient who unable to tolerate aflibercept, 5-FU or irinotecan.
21)Patient with a severe stenosis due to primary CRC. Primary patient with CRC resection or colostomy can be included.
22)Patients with hepatic cirrhosis or active hepatitis.
23)Patients whom a lead investigator or primary physician deems are not appropriate for this study.

Related Information

• Primary Sponsor: Oki Eiji
• Source(s) of Monetary Support: Sanofi K.K.