Irinotecan, TAS-102 Plus Bevacizumab as a Third-Line or Beyond Therapy in mCRC Patients

The mCRC patients who are refractory to standard therapies and need a third-line or beyond therapy are eligible. Patients who previously received irinotecan while progressing during maintenance therapy are also eligible.

These patients received an intravenous infusion of irinotecan (150mg/m2 on day 1) plus bevacizumab (5 mg/kg on day 1) and an oral administration of TAS-102(30 mg/m2 given bid on days 1-5), repeated every 14 days.

The primary endpoint was the objective response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.

Inclusion criteria

• Colorectal adenocarcinoma confirmed histologically or histopathologically.
• Patients were clinically diagnosed with metastatic colorectal cancer based on computed tomography (CT) scan and magnetic resonance imaging (MRI) according to AJCC 8th edition.
• Patients must have received standard therapy for mCRC and is refractory or intolerant to those therapies.
• Age ≥18 and ≤70.
• ECOG physical status score is 0 or 1, and no obvious deterioration within 2 weeks prior to use on Day 1 of Cycle 1.
• Appropriate organ function according to the following laboratory test values:

• Hemoglobin value ≥90g/L.
• White blood cell count ≥3.5*109/L.
• Absolute neutrophil count ≥1.5*109/L.
• Platelet count ≥100*109/L.
• Serum creatinine ≤ upper limit of normal (ULN) or creatinine clearance ≥60ml/min.
• Total serum bilirubin ≤1.5* upper normal limit (ULN).
• Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤2.5* upper limit of normal value (ULN).
• Signed the informed consent.

Exclusion criteria

• The pathological types were squamous carcinoma, neuroendocrine carcinoma, adenosquamous carcinoma, and other histological types except adenocarcinoma.
• Patients who had shown hypersensitivity to Irinotecan and Trifluridine/tipiracil (TAS-102) or any other component of them. Patients who previously received irinotecan while disease progressed. However, patients who previously received irinotecan while progressing during maintenance therapy are eligible.
• Known hypersensitivity to Bevacizumab or hypersensitivity to any other component of Bevacizumab.
• Patients unable to swallow or lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.
• Patients had recurrent episodes of bleeding (risk of gastrointestinal bleeding) or received transfusions in the previous 2 weeks.
• Major surgery in the previous 4 weeks. (Biopsy is excluded)
• Previous or concurrent cancer diagnosed within 5 years prior to study inclusion, except for curatively treated in situ cervical cancer, non-melanoma skin cancer, basal cell carcinoma, benign prostate cancer, ductal carcinoma in situ, well-differentiated thyroid cancers and superficial bladder tumors: staged Ta (non-invasive tumor), Tis (carcinoma in situ), and T1 (tumor with lamina propria invasion). Carcinomas that can be cured by adequate treatment are also excluded.
• History of abdominal fistula, gastro-intestinal perforation, intestinal obstruction, chronic diarrhea or inflammatory bowel disease including Crohns disease and ulcerative colitis within 6 months prior to the first study treatment.
• Patients with severe cardiac dysfunction, such as LVEF< 50%, CHF≥ grade 2, severe/unstable angina, history of stroke or transient ischemic attack or myocardial infarction in the previous 6 months.
• Uncontrolled hypertension (systolic blood pressure >160 mmHg or diastolic pressure >100 mmHg despite treatment) and uncontrolled diabetes (fasting plasma glucose > 8.9 mmol/l).
• Patients with a history of ventricular tachycardia, torsades de pointes, prolonged QTc, complete left bundle branch block or third-degree atrioventricular conduction block..
• Patients with active hepatitis B, hepatitis C, syphilis or human immunodeficiency virus infection.
• Arterial or venous thrombotic or embolic events such as deep vein thrombosis, and pulmonary embolism within 6 months of starting study treatment (catheter-related thrombosis is excluded).
• Patients with active pulmonary tuberculosis were taking anti-tuberculosis treatment or have taken anti-tuberculosis treatment within 12 months of starting study treatment.
• Patients with severe primary respiratory diseases, interstitial lung disease, or history of pneumonitis.
• Patients with current active infections requiring anti-infection treatment within 2 weeks of starting study treatment.
• Patients with a history of psychiatric drug abuse or a history of drug abuse.
• Pregnant or lactating women.
• Patients of childbearing potential are unwilling to practice contraception.