Phase III Study of Trifluridine/Tipiracil With and Without Bevacizumab in Refractory Metastatic Colorectal Cancer Patients

This study is designed as an international, open-label, controlled two-arm, randomized phase III comparison study evaluating the efficacy and safety of trifluridine/tipiracil in combination with bevacizumab versus trifluridine/tipiracil monotherapy in patients with refractory mCRC.

This is an international, open-label, controlled two-arm, randomised phase III study evaluating the efficacy and safety of trifluridine/tipiracil in combination with bevacizumab versus trifluridine/tipiracil monotherapy in patients with refractory mCRC. The analysis will be done after 331 events are reported. In order to observe this number of events, 490 patients will be randomised (1:1) to receive trifluridine/tipiracil in combination with bevacizumab (experimental arm) or trifluridine/tipiracil monotherapy (control arm).

Eligibility Criteria:
Inclusion Criteria:

1. Has histologically confirmed unresectable adenocarcinoma of the colon or rectum (all other histological types are excluded).
2. RAS status must have been previously determined (mutant or wild-type) based on local assessment of tumor biopsy.
3. Has received a maximum of 2 prior chemotherapy regimens for the treatment of advanced colorectal cancer and had demonstrated progressive disease or intolerance to their last regimen.
4. Has measurable or non-measurable disease as defined by RECIST version 1.1
5. Is able to swallow oral tablets.
6. Estimated life expectancy ≥12 weeks.
7. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1

Exclusion Criteria:

1. More than 2 prior chemotherapy regimens for the treatment of advanced colorectal cancer.
2. Pregnancy, lactating female or possibility of becoming pregnant during the study.
3. Patients currently receiving or having received anticancer therapies within 4 weeks prior to randomization.
4. Has not recovered from clinically relevant non-hematologic CTCAE grade ≥ 3 toxicity of previous anticancer therapy prior to randomization (excluding alopecia, and skin pigmentation).
5. Has symptomatic central nervous system metastases that are neurologically unstable or requiring increasing doses of steroids to control CNS disease.
6. Has severe or uncontrolled active acute or chronic infection.
7. Has active or history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension.
8. Known Hepatitis B or Hepatitis C Virus infection.
9. Known carriers of HIV antibodies.
10. Confirmed uncontrolled arterial hypertension (defined as systolic blood pressure ≥ 150 mm Hg and/or diastolic blood pressure ≥ 100 mm Hg) or uncontrolled or symptomatic arrhythmia.
11. Deep arterial thromboembolic events including cerebrovascular accident or myocardial infarction within the last 6 months prior to randomization.
12. Treatment with any of the following within the specified time frame prior to randomization:

    * major surgery within 4 weeks prior to randomisation (the surgical incision should be fully healed prior to study drug administration), or has not recovered from side effects of previous surgery, or patient that may require major surgery during the study
    * Prior radiotherapy if completed less than 4 weeks before randomisation, except if provided as a short course for symptoms palliation only.
    * Drainage for ascites, pleural effusion or pericardial fluid within 4 weeks prior to randomization
13. Other clinically significant medical conditions.
14. Other malignancies.