Fruquintinib Plus Checkpoint Inhibitor Combined or Sequential TAS-102 in Colorectal Cancer Patients Who Progressed on Second-line Standard Therapy: a Prospective, Multi-cohort, Single-centered, Phase Ib/II Study

Fruquintinib Plus Checkpoint Inhibitor Combined or Sequential Trifluridine/Tipiracil(TAS-102) Based Regimen in Colorectal Cancer Patients Who Progressed on Second-line Standard Therapy: a Prospective, Multi-cohort, Single-centered, Phase Ib/II Study

Colorectal cancer (CRC) is the fourth leading cause of cancer death worldwide, claiming approximately 900,000 lives annually. In China, CRC has become one of the top three most common cancers, with about 555,000 new cases and 286,000 deaths reported in 2020.

For patients with advanced metastatic colorectal cancer (mCRC), chemotherapy remains the main treatment approach. While first and second-line treatments have improved survival rates, treatment options become very limited after these initial therapies fail.

Current third-line options include single-drug treatments with fruquintinib, regorafenib, or Trifluridine/Tipiracil(TAS-102). Although these medications can extend survival, their effectiveness still needs improvement.

Additionally, approximately 95% of mCRC patients have a tumor type [Proficient Mismatch Repair(pMMR)/Microsatellite Stable(MSS)] that responds poorly to immunotherapy alone, making it crucial to find ways to expand the benefits of immunotherapy to more patients.

This study aims to evaluate the effectiveness and safety of combining:

Fruquintinib (a targeted therapy) Immune checkpoint inhibitors (immunotherapy) TAS-102 (oral chemotherapy)in patients with unresectable metastatic colorectal cancer who have failed standard second-line treatments.

By exploring combination therapy strategies, this research hopes to improve treatment response rates, extend overall survival and provide new treatment options for patients with limited choices

Study Overview

• Status: Active, not recruiting
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: Fruquintinib plus immunocheckpoint inhibitor plus trifluridine/tipiracil; Drug: Fruquintinib plus immunocheckpoint inhibitor followed by trifluridine/tipiracil plus bevacizumab

• Study Type: Interventional
• Enrollment (Estimated): 106
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Tianjin Municipality
    • Tianjin, Tianjin Municipality, China, 300202
      • Tianjin cancer hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Fully informed about this study and voluntarily signed the informed consent form;
• Age 18-75 years (inclusive);
• Histologically confirmed unresectable metastatic colorectal cancer;
• Confirmed pMMR (proficient mismatch repair) status without protein loss, as determined by:PCR testing showing microsatellite stable (MSS) or low microsatellite instability (MSI-L), OR Immunohistochemistry (IHC) demonstrating intact DNA mismatch repair (MMR) protein expression (including MLH1, MSH2, MSH6, and PMS2);
• Failed or intolerant to two prior lines of standard systemic therapy for metastatic colorectal cancer;
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;
• Body Mass Index (BMI) ≥18 kg/m²;
• Life expectancy ≥3 months;
• Adequate organ function as defined below (no blood components or growth factors allowed within 14 days prior to enrollment):
• Hematologic Function:

Absolute neutrophil count (ANC) ≥1.5×10⁹/L; White blood cell count (WBC) ≥4.0×10⁹/L; Platelet count ≥100×10⁹/L; Hemoglobin ≥90 g/L; -Hepatic Function: Total bilirubin (TBIL) ≤1.5× upper limit of normal (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5×ULN;

-Renal Function: Blood urea nitrogen (BUN) and creatinine (Cr) ≤1.5×ULN; Creatinine clearance (CCr) ≥50 mL/min;

-Cardiac Function: Left ventricular ejection fraction (LVEF) ≥50%; QT interval corrected by Fridericia's formula (QTcF) <470 ms;

-Coagulation Function: International normalized ratio (INR) ≤1.5×ULN; Activated partial thromboplastin time (APTT) ≤1.5×ULN;

• Women of childbearing potential must use effective contraception;
• Good compliance and willing to cooperate with follow-up visits.

Exclusion Criteria:

• Unable to comply with the study protocol or study procedures;
• Prior treatment with TAS-102 (trifluridine/tipiracil);
• Prior treatment with VEGFR inhibitors;
• Prior treatment with immune checkpoint inhibitors;
• Concurrent use of any other investigational drugs, or participation in another clinical trial with investigational drug treatment within 4 weeks prior to enrollment;
• Vaccination with inactivated vaccines within 4 weeks prior to enrollment or planned vaccination during the study period;
• Major surgery, severe traumatic injury, fracture, or ulcer within 4 weeks prior to enrollment;
• Blood transfusion, blood products, or hematopoietic factors (such as albumin, granulocyte colony-stimulating factor [G-CSF], etc.) within 28 days prior to enrollment;
• Alcohol or drug abuse within 4 weeks prior to enrollment;
• Any factors affecting oral drug administration;
• Concurrent presence of any of the following conditions:
• Uncontrolled hypertension, coronary artery disease, arrhythmia, or heart failure;
• Uncontrolled severe concurrent infection resulting in disability;
• Proteinuria ≥2+ (1.0 g/24 h);
• Evidence or history of bleeding tendency within 2 months prior to enrollment, regardless of severity;
• Arterial/venous thromboembolic events within 12 months prior to first treatment, such as cerebrovascular accident (including transient ischemic attack), etc.;
• Acute myocardial infarction, acute coronary syndrome, or coronary artery bypass grafting (CABG) within 6 months prior to first treatment;
• Fracture or long-term unhealed wounds;
• Coagulation dysfunction, bleeding tendency, or currently receiving anticoagulant therapy;
• Evidence of central nervous system (CNS) metastasis, or accompanied by severe malignant pleural effusion or ascites;
• Other malignancies within 5 years prior to enrollment, except for basal cell or squamous cell carcinoma of the skin after curative surgery, or carcinoma in situ of the cervix;
• Active autoimmune disease or history of autoimmune disease within 4 weeks prior to enrollment;
• Prior allogeneic bone marrow transplantation or organ transplantation;
• Known hypersensitivity to study drugs or any of their excipients;
• Unresolved toxicities greater than CTCAE v5.0 Grade 1 from prior anti-cancer therapy, excluding alopecia, lymphopenia, and oxaliplatin-induced neurotoxicity ≤Grade 2;
• Any other disease, clinically significant metabolic abnormality, physical examination abnormality, or laboratory abnormality that, in the investigator's judgment, provides reasonable suspicion that the patient has a condition unsuitable for the use of the study drug (e.g., epileptic seizures requiring treatment), or that would affect the interpretation of study results, or would place the patient at high risk;
• Pregnant or breastfeeding women;
• Any patient deemed unsuitable for enrollment in this study by the investigator.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fruquintinib plus immunocheckpoint inhibitor plus trifluridine/tipiracil	Drug: Fruquintinib plus immunocheckpoint inhibitor plus trifluridine/tipiracil; Fruquintinib plus immunocheckpoint inhibitor plus trifluridine/tipiracil
Experimental: Fruquintinib plus immunocheckpoint inhibitor followed by trifluridine/tipiracil plus bevacizumab	Drug: Fruquintinib plus immunocheckpoint inhibitor followed by trifluridine/tipiracil plus bevacizumab; Fruquintinib plus immunocheckpoint inhibitor followed by trifluridine/tipiracil plus bevacizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
RP2D	Recommended phase 2 dose	From enrollment to the end of treatment at 4 week
Overall Survival (OS)	Time from randomization/enrollment to death from any cause	Up to 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progress-free Survival (PFS)	Time from randomization/enrollment to first documented disease progression (per RECIST v1.1) or death from any cause, whichever occurs first	Assessed every 8 weeks, up to 12 months
Objective Response Rate (ORR)	The proportion of patients who achieve a confirmed complete response (CR) or partial response (PR) as their best overall response, as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1	Tumor assessments performed at baseline, then every 8 weeks (±7 days) from the date of first dose until radiographic disease progression or death, assessed up to approximately 12 months
Duration of Response (DoR)	Time from first documented response (CR/PR) to disease progression or death	Up to 12 months
Incidence of AEs	Number and percentage of participants experiencing adverse events graded by NCI-CTCAE v5.0	by NCI-CTCAE v5.0. From first dose up to 30 days after last dose
Incidence of SAEs	Number and percentage of participants experiencing serious adverse events	From informed consent up to 30 days after last dose
Number of participants with Laboratory abnormalities	Incidence of clinically significant laboratory parameter changes per NCI-CTCAE v5.0	From baseline up to 30 days after last dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker Analysis for Efficacy Prediction	To explore potential predictive biomarkers associated with treatment efficacy, including: Blood-based biomarkers (CEA, CTCs, VEGF)	Baseline, during treatment (every 8 weeks), and at disease progression, up to 24 months
Tumor tissue biomarkers (TMB, DNA methylation status)	Biomarker Analysis for Efficacy Prediction	Baseline, during treatment (every 8 weeks), and at disease progression, up to 24 months
Clinical characteristics (sex, metastatic sites)		Baseline, during treatment (every 8 weeks), and at disease progression, up to 24 months

Collaborators and Investigators

• Sponsor: Tianjin Medical University Cancer Institute and Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2023
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: February 26, 2026
• First Submitted That Met QC Criteria: March 19, 2026
• First Posted (Actual): March 24, 2026

Study Record Updates

• Last Update Posted (Actual): March 24, 2026
• Last Update Submitted That Met QC Criteria: March 19, 2026
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: metastatic colorectal cancer; Microsatellite Stable; Trifluridine/tipiracil; fruquintinib
• 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: CRC later-line

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Informed consent limitations: Original consent may not have covered IPD sharing with external researchers

Drug and device information, study documents

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