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

NCT07491159 | Active Not Recruiting Phase 1

• 1 other identifier: CRC later-line
• Study Type: interventional
• Target: 106
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Colorectal Cancer

Keywords

fruquintinib; Trifluridine/tipiracil; Microsatellite Stable; metastatic colorectal cancer

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (6)

• Progress-free Survival (PFS)

  Assessed every 8 weeks, up to 12 months

• Objective Response Rate (ORR)

  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)

  Up to 12 months

• Incidence of AEs

  by NCI-CTCAE v5.0. From first dose up to 30 days after last dose

• Incidence of SAEs

  From informed consent up to 30 days after last dose

Other Outcomes (3)

• Biomarker Analysis for Efficacy Prediction

  Baseline, during treatment (every 8 weeks), and at disease progression, up to 24 months

• Tumor tissue biomarkers (TMB, DNA methylation status)

  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

Study Arms (2)

Fruquintinib plus immunocheckpoint inhibitor plus trifluridine/tipiracil

EXPERIMENTAL

Fruquintinib plus immunocheckpoint inhibitor plus trifluridine/tipiracil

Drug: Fruquintinib plus immunocheckpoint inhibitor plus trifluridine/tipiracil

Fruquintinib plus immunocheckpoint inhibitor followed by trifluridine/tipiracil plus bevacizumab

EXPERIMENTAL

Fruquintinib plus immunocheckpoint inhibitor followed by trifluridine/tipiracil plus bevacizumab

Drug: Fruquintinib plus immunocheckpoint inhibitor followed by trifluridine/tipiracil plus bevacizumab

Interventions

Fruquintinib plus immunocheckpoint inhibitor plus trifluridine/tipiracil DRUG

Fruquintinib plus immunocheckpoint inhibitor plus trifluridine/tipiracil

Fruquintinib plus immunocheckpoint inhibitor plus trifluridine/tipiracil

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

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;

You may not qualify if:

• 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;

Sponsors & Collaborators

• Tianjin Medical University Cancer Institute and Hospital: lead

Study Sites (1)

Tianjin Cancer Hospital

Tianjin, Tianjin Municipality, 300202, China

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

HMPL-013; Trifluridine; tipiracil; Bevacizumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Thymidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 26, 2026
• First Posted: March 24, 2026
• Study Start: July 1, 2023
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): December 30, 2026
• Last Updated: March 24, 2026

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)