Trifluridine/Tipiracil Plus Fruquintinib vs. Trifluridine/Tipiracil Plus Bevacizumab in Refractory Metastatic Colorectal Cancer: A Randomized, Controlled, Open-Label, Non-Inferiority Trial

Overview

This study is an investigator-initiated, prospective, multicenter, randomized, controlled, open-label, non-inferiority trial designed to evaluate the efficacy and safety of trifluridine/tipiracil plus fruquintinib versus trifluridine/tipiracil plus bevacizumab in the treatment of refractory metastatic colorectal cancer.

Detailed description

A total of 236 patients will be enrolled in this investigator-initiated, prospective, multicenter, randomized, controlled, open-label, non-inferiority trial.

Experimental group:

Trifluridine/tipiracil 35 mg/m² orally twice daily on days 1-5 and 8-12, repeated every 4 weeks, plus fruquintinib 4 mg orally once daily for 3 weeks followed by 1 week off, repeated every 4 weeks.

Control group:

Trifluridine/tipiracil 35 mg/m² orally twice daily on days 1-5 and 8-12, repeated every 4 weeks, plus bevacizumab 5 mg/kg intravenously on day 1 every 2 weeks.

Interventions

• Drug Trifluridine/tipiracil plus fruquintinib
  Trifluridine/tipiracil 35 mg/m² orally twice daily on days 1-5 and 8-12, repeated every 4 weeks, plus fruquintinib 4 mg orally once daily for 3 weeks followed by 1 week off, repeated every 4 weeks.
• Drug trifluridine/tipiracil plus bevacizumab
  Trifluridine/tipiracil 35 mg/m² orally twice daily on days 1-5 and 8-12, repeated every 4 weeks, plus bevacizumab 5 mg/kg intravenously on day 1 every 2 weeks.

Primary outcome measures

• PFS [Time frame: Time from the date of randomization to the first occurrence of disease progression (as assessed by the investigator according to RECIST v1.1) or death, whichever occurs first,up to 2 years]

Secondary outcome measures (4)

• OS [Time frame: Time from the date of randomization to death from any cause up to 3 years]
• ORR [Time frame: from randomization up to progressive disease or EOT due to any cause, up to 2 years]
• DCR [Time frame: from randomization up to progressive disease or EOT due to any cause, up to 2 years]
• Safety and tolerance [Time frame: from first dose to within 30 days after the last dose]

Eligibility criteria

Inclusion criteria

• All study participants must sign the informed consent form before any study-related procedures are initiated.
• Aged 18-75 years, both males and females.
• Histologically confirmed unresectable colorectal cancer.
• RAS status known (mutant or wild-type).
• Progression or intolerance after at least two prior systemic regimens that must have contained fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy plus anti-VEGF therapy and/or anti-EGFR therapy.
• At least one measurable lesion per RECIST v1.1.
• Able to swallow oral tablets or capsules.
• Estimated life expectancy ≥ 12 weeks.
• ECOG performance status 0-1.
• Adequate major organ function (within 7 days before randomization):

Absolute neutrophil count ≥ 1.5 × 10⁹/L Platelet count ≥ 75 × 10⁹/L Hemoglobin ≥ 90 g/L (no transfusion within 7 days) Creatinine clearance ≥ 60 mL/min (Cockcroft-Gault formula) Total bilirubin ≤ 1.5 × upper limit of normal (ULN) AST and ALT ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases present) Urinalysis showing proteinuria ≤ 1+ or 24-h urine protein < 1 g INR or PT ≤ 1.5 × ULN (acceptable if on anticoagulation and PT within intended therapeutic range)

• Women of child-bearing potential must have a negative serum pregnancy test within 7 days before randomization; all participants and their partners must agree to use highly effective contraception from screening through at least 6 months after the last dose of study medication.

Exclusion criteria

• 1.Prior treatment with trifluridine/tipiracil, fruquintinib, or any other VEGF-receptor tyrosine-kinase inhibitor (e.g., apatinib, regorafenib, anlotinib).

2.Pregnant or lactating women, or women who may become pregnant during the study.

3.Anti-cancer therapy given ≤ 4 weeks before randomization (or not yet completed).

4.Clinically relevant non-haematological CTCAE grade ≥ 3 toxicity from prior anti-cancer therapy that has not resolved to ≤ grade 1 (except alopecia and skin pigmentation).

5.Symptomatic central-nervous-system metastases, unstable neurological status, or requirement for an increased steroid dose to control CNS disease.

6.Severe or uncontrolled acute or chronic active infection. 7.History of active or interstitial lung disease, pneumonitis, or pulmonary arterial hypertension.

8.Clinically significant active hepatitis of any cause, including but not limited to hepatitis B or C.

9.Known HIV-positive status. 10.Uncontrolled hypertension (systolic BP ≥ 150 mmHg and/or diastolic BP ≥ 100 mmHg), uncontrolled arrhythmia, or symptomatic arrhythmia.

11.Arterial thrombo-embolic event ≤ 6 months before randomization, including cerebrovascular accident or myocardial infarction.

12.Major surgery ≤ 4 weeks before randomization (surgical incision must be fully healed before study drug administration), not yet recovered from previous surgery, or major surgery anticipated during the study.

13.Radiotherapy ≤ 2 weeks before randomization, except short-course palliative radiotherapy for symptom relief.

14.Any other clinically significant medical condition that, in the investigator's opinion, would compromise patient safety or study integrity.

15.Concurrent or previous malignancy within 5 years, except adequately treated basal-cell or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• the first affiliated hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080 — Guangzhou

Identifiers

NCT: NCT07261709 · TAS-FUR

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗