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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Refractory Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: Trifluridine/tipiracil plus fruquintinib; Drug: trifluridine/tipiracil plus bevacizumab

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.

• Study Type: Interventional
• Enrollment (Estimated): 236
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jianjun Peng; Phone Number: +8613602263939; Email: pjianj@mail.sysu.edu.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China
      • the first affiliated hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080
      • Contact: Peng; Phone Number: +8613602263939; Email: pjianj@mail.sysu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. All study participants must sign the informed consent form before any study-related procedures are initiated.
2. Aged 18-75 years, both males and females.
3. Histologically confirmed unresectable colorectal cancer.
4. RAS status known (mutant or wild-type).
5. 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.
6. At least one measurable lesion per RECIST v1.1.
7. Able to swallow oral tablets or capsules.
8. Estimated life expectancy ≥ 12 weeks.
9. ECOG performance status 0-1.

10. 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)

11. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Trifluridine/tipiracil plus fruquintinib	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.
Active Comparator: Trifluridine/tipiracil plus bevacizumab	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS	Progression-free Survival	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

Outcome Measure	Measure Description	Time Frame
DCR	Disease Control Rate	from randomization up to progressive disease or EOT due to any cause, up to 2 years
ORR	Objective Response Rate	from randomization up to progressive disease or EOT due to any cause, up to 2 years
Safety and tolerance	Safety and tolerance evaluated by incidence, severity and outcomes of adverse events (AEs) and categorized by severity in accordance with the NCI CTC AE Version 5.0	from first dose to within 30 days after the last dose
OS	Overall Survival	Time from the date of randomization to death from any cause up to 3 years

Collaborators and Investigators

• Sponsor: Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2025
• Primary Completion (Estimated): October 30, 2027
• Study Completion (Estimated): March 30, 2028

Study Registration Dates

• First Submitted: November 21, 2025
• First Submitted That Met QC Criteria: November 21, 2025
• First Posted (Estimated): December 3, 2025

Study Record Updates

• Last Update Posted (Estimated): December 3, 2025
• Last Update Submitted That Met QC Criteria: November 21, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Deoxyribonucleosides; Thymidine; Bevacizumab; Trifluridine; HMPL-013; tipiracil
• Other Study ID Numbers: TAS-FUR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No