FOLFOX Chemotherapy Combined With Fruquintinib and Serplulimab as First-Line Conversion Therapy for Initially Unresectable pMMR/MSS Colorectal Cancer

Exploratory Clinical Study of FOLFOX Chemotherapy Combined With Fruquintinib and Serplulimab as First-Line Conversion Therapy for Initially Unresectable pMMR/MSS Colorectal Cancer

To evaluate the efficacy and safety of immune checkpoint inhibitor-based combination therapy with targeted therapy and chemotherapy in patients with locally advanced unresectable or metastatic colorectal cancer.

Study Overview

• Status: Not yet recruiting
• Conditions: Colorectal Cancer Microsatellite Stable (MSS); Colorectal Cancer (Locally Advanced or Metastatic)
• Intervention / Treatment: Drug: Serplulimab; Drug: Fruquintinib; Drug: mFOLFOX6 (oxaliplatin, calcium folinate, and 5-FU)

Detailed Description

1.1 Overview of Colorectal Cancer Colorectal cancer (CRC) is the third most common malignancy worldwide and a leading cause of cancer-related mortality. In China, CRC incidence and mortality continue to rise, with a high proportion of patients diagnosed at advanced stages. While radical surgery remains the cornerstone of curative treatment, many patients present with unresectable disease, and long-term survival remains poor.

Immune checkpoint inhibitors targeting PD-1/PD-L1 have transformed cancer therapy; however, their benefit in CRC is largely confined to dMMR/MSI-H tumors, which account for only 10-15% of cases. The majority of CRC patients with pMMR/MSS disease derive little benefit from immunotherapy alone.

1.2 Conversion Therapy in Colorectal Cancer Conversion therapy aims to downstage initially unresectable tumors through systemic treatment, enabling surgical resection. In metastatic CRC, successful conversion followed by radical resection can significantly improve long-term survival, with 5-year survival rates reaching 30-50% in selected patients.

1.3 Immunotherapy and Targeted Therapy in pMMR/MSS CRC pMMR/MSS tumors are considered "cold tumors" with low tumor mutational burden and limited immune cell infiltration. Multiple trials have shown minimal efficacy of PD-1 inhibitors alone in this population. Combination strategies incorporating chemotherapy and anti-angiogenic agents may enhance immune response and improve outcomes.

1.4 Serplulimab Serplulimab is a fully humanized anti-PD-1 IgG4 monoclonal antibody with high affinity, slow dissociation, low immunogenicity, and favorable safety characteristics. It has been approved in China for multiple indications including lung cancer and esophageal squamous cell carcinoma, with demonstrated survival benefits.

1.5 Fruquintinib Fruquintinib is a highly selective small-molecule VEGFR inhibitor targeting VEGFR-1, -2, and -3. It inhibits tumor angiogenesis with high potency and manageable toxicity. Fruquintinib has been approved for metastatic colorectal cancer refractory to standard therapies.

1.6 Rationale for This Study Based on strong preclinical and clinical evidence supporting the synergistic effects of immunotherapy, anti-angiogenic therapy, and chemotherapy, this study is the first to explore serplulimab combined with fruquintinib and FOLFOX chemotherapy as first-line conversion therapy in pMMR/MSS colorectal cancer.

• Study Type: Interventional
• Enrollment (Estimated): 42
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ye Xu; Phone Number: +86 18017312565; Email: yexu@shmu.edu.cn

Study Locations

• China
  • Xuhui
    • Shanghai, Xuhui, China
      • Fudan University Shanghai Cancer Center
      • Contact: Ye Xu; Phone Number: +86 18017312565; Email: yexu@shmu.edu.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age 18-75 years;
• Histologically confirmed adenocarcinoma of colorectal cancer, initially unresectable locally advanced or metastatic/recurrent disease;
• Expected survival ≥12 weeks;
• No prior systemic antitumor therapy for colorectal cancer;
• Confirmed pMMR by IHC or MSS/MSI-L by PCR or NGS;
• ECOG PS 0-1;
• At least one measurable lesion per RECIST v1.1;
• Adequate organ and bone marrow function;
• Controlled viral hepatitis status as specified;
• Signed written informed consent.

Exclusion Criteria:

• Prior immune checkpoint inhibitor therapy;
• CNS or leptomeningeal metastases;
• Uncontrolled cardiovascular disease or hypertension;
• Active autoimmune disease requiring systemic therapy;
• Active infection including tuberculosis;
• Recent major surgery;
• Pregnancy or lactation;
• Any condition deemed by investigators to compromise safety or study compliance.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Conversion Therapy; Conversion Therapy (≤6 months) Fruquintinib: 4 mg orally once daily, Days 1-21, every 4 weeks mFOLFOX6: Oxaliplatin 85 mg/m² IV q2w Leucovorin 400 mg/m² IV q2w 5-FU 400 mg/m² IV bolus Day 1 5-FU 1200 mg/m²/day continuous IV infusion Days 2-3 Serplulimab: 200 mg IV Day 1, q2w Fruquintinib must be stopped ≥2 weeks prior to surgery and resumed ≥4 weeks postoperatively.

Drug: Serplulimab; Serplulimab: 200 mg IV Day 1, q2w; Drug: Fruquintinib; Fruquintinib: 4 mg orally once daily, Days 1-21, every 4 weeks; Drug: mFOLFOX6 (oxaliplatin, calcium folinate, and 5-FU); Oxaliplatin 85 mg/m² IV q2w Leucovorin 400 mg/m² IV q2w 5-FU 400 mg/m² IV bolus Day 1 5-FU 1200 mg/m²/day continuous IV infusion Days 2-3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Conversion Rate to Surgery	≤ 6 months
Objective Response Rate	≤6 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival		6 months
Progression-Free Survival		6 months
Disease Control Rate		6 months
Depth of Response	Depth of Response (DpR): defined as the maximum percentage reduction of tumor target lesions compared with baseline (pre-treatment) during the course of tumor treatment.	6 months
Early Tumor Shrinkage	Early Tumor Shrinkage (ETS): defined as a predefined percentage reduction in the sum of the longest diameters of target lesions within a specified time period after the initiation of treatment.	6 months
R0 Resection Rate		6 months

Collaborators and Investigators

• Sponsor: Ye Xu

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): January 31, 2027
• Study Completion (Estimated): January 31, 2027

Study Registration Dates

• First Submitted: February 24, 2026
• First Submitted That Met QC Criteria: February 28, 2026
• First Posted (Actual): March 3, 2026

Study Record Updates

• Last Update Posted (Actual): March 3, 2026
• Last Update Submitted That Met QC Criteria: February 28, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Neoplastic Processes; Pathological Conditions, Signs and Symptoms; Colorectal Neoplasms; Neoplasm Metastasis; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Enzymes and Coenzymes; Coordination Complexes; Pyrimidines; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Uracil; Pyrimidinones; Coenzymes; Oxaliplatin; Fluorouracil; Leucovorin; HMPL-013
• Other Study ID Numbers: FRUTISCO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No