Savolitinib Plus Cetuximab and FOLFOX Chemotherapy for RAS/BRAF Wild-type Metastatic Colorectal Cancer

Savolitinib Plus Cetuximab and FOLFOX Chemotherapy Versus Cetuximab and FOLFOX Chemotherapy as First-line Treatment for RAS/BRAF Wild-type Metastatic Colorectal Cancer: a Prospective, Randomized, Controlled, Multicenter, Open-label Study

The goal of this clinical trial is to learn if adding savolitinib to cetuximab plus FOLFOX chemotherapy works as a first-line treatment for patients with RAS/BRAF wild-type metastatic colorectal cancer, and to evaluate its safety. The main questions it aims to answer are:

Does the addition of savolitinib improve the objective response rate (ORR) compared to cetuximab plus FOLFOX alone?

What medical problems (adverse events) do participants experience when taking savolitinib in combination with cetuximab and FOLFOX?

Researchers will compare savolitinib plus cetuximab and FOLFOX (experimental group) versus cetuximab and FOLFOX alone (control group) to see if the triplet regimen provides better tumor response and survival outcomes.

Participants will:

Take oral savolitinib once daily in repeated 14-day cycles (or receive control treatment), combined with weekly cetuximab and bi-weekly FOLFOX chemotherapy

Visit the clinic every 2 weeks or 4 weeks for treatment administration, safety monitoring, and laboratory tests

Undergo tumor imaging assessments every 8 weeks (4 cycles) to evaluate treatment response and disease progression

Have regular follow-up visits for 30 days after the last dose, and then every 3 months for survival follow-up

Study Overview

• Status: Not yet recruiting
• Conditions: Colorectal Cancer (CRC)
• Intervention / Treatment: Drug: Savolitinib plus cetuximab and FOLFOX chemotherapy; Drug: Cetuximab and FOLFOX chemotherapy

• Study Type: Interventional
• Enrollment (Estimated): 138
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Jianmin Xu, Phd; Phone Number: 021-64041990; Email: xujmin@yahoo.com.cn

Study Locations

• China
  • Shanghai, China, 200000
    • Fudan University Shanghai Cancer Center
    • Contact: Ye Xu, Phd; Phone Number: 021-64175590; Email: yexu@shmu.edu.cn
  • Shanghai, China, 200000
    • Zhongshan Hospital, Fudan University
    • Contact: Jianmin Xu, Phd; Phone Number: 021-64041990; Email: xujmin@yahoo.com.cn
  • Shanghai, China, 200000
    • Changhai Hospital
    • Contact: Wei Zhang, Phd; Phone Number: 021-31166666; Email: weizhang2000cn@163.com
  • Shanghai, China, 200000
    • Renji Hospital, Shanghai Jiao Tong University, School of Medicine
    • Contact: Zizhen Zhang, Phd; Phone Number: 021-58752345; Email: zhangzizhen@renji.com
  • Shanghai, China, 200000
    • Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine
    • Contact: Tao Zhang, Phd; Phone Number: 021-64370045; Email: zhangtao@ruijin.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Voluntarily sign the informed consent form after fully understanding this study;
2. Aged 18 to 75 years (inclusive), male or female;
3. Have at least one measurable lesion (RECIST 1.1);
4. Histologically confirmed unresectable locally advanced or metastatic colorectal cancer;
5. pMMR by immunohistochemistry or unknown MMR protein expression status;
6. KRAS/NRAS and BRAF all wild-type;
7. c-MET IHC intensity score 2+ or 3+ in ≥50% of tumor cells in the primary lesion; or positive by FISH; or NGS copy number ≥3;
8. No prior systemic therapy (Note: prior neoadjuvant or adjuvant chemotherapy is allowed if disease progression/recurrence occurred during or ≥6 months after completion of such therapy);
9. ECOG performance status 0-1;
10. Life expectancy ≥12 weeks;

11. Laboratory parameters (within 14 days without blood transfusion):

    • Absolute neutrophil count ≥1.5×10⁹/L, platelet count ≥100×10⁹/L, hemoglobin ≥9 g/dL;
    • Liver function: AST and ALT ≤2.5×ULN, total bilirubin ≤1.5×ULN; if liver metastases present, AST and ALT ≤5×ULN;
    • Renal function: serum creatinine ≤1.5×ULN, creatinine clearance (CCr) ≥60 mL/min;
12. Fertile male or female patients voluntarily agree to use effective contraceptive methods during the study and for 6 months after the last dose of study treatment.

Exclusion Criteria:

1. Prior treatment with anti-EGFR monoclonal antibody therapy;
2. Prior treatment with c-MET small molecule inhibitors or monoclonal antibodies targeting c-MET or HGF;
3. Received approved or investigational systemic anti-tumor therapy within 4 weeks prior to enrollment;
4. Participated in another clinical trial of a drug not yet approved or marketed in China and received the investigational drug within 4 weeks prior to enrollment;
5. Underwent any surgery or invasive treatment or procedure (except venous catheterization, puncture drainage, etc.) within 4 weeks prior to enrollment;
6. INR >1.5 or APTT >1.5×ULN;
7. Clinically significant electrolyte abnormalities as judged by the investigator;
8. Uncontrolled hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg);
9. Poorly controlled blood glucose (FBG ≥10 mmol/L);
10. Any disease or condition affecting drug absorption, or inability to take oral savolitinib;
11. Active gastric or duodenal ulcer, ulcerative colitis, or other gastrointestinal diseases, or active bleeding from an unresected tumor, or other conditions that may cause gastrointestinal bleeding or perforation within 28 days prior to enrollment;
12. History or evidence of significant bleeding tendency within 3 months prior to enrollment (bleeding >30 mL within 3 months, hematemesis, melena, hematochezia), hemoptysis (>5 mL fresh blood within 4 weeks), or thromboembolic events within 12 months;
13. Clinically significant cardiovascular disease (e.g., acute myocardial infarction within 6 months, unstable angina, heart failure NYHA class >2, ventricular arrhythmia requiring medication, LVEF <50%);
14. Other malignancy within the past 5 years (except adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix);

15. Active or uncontrolled serious infection:

    • Known HIV infection;
    • Known clinically significant liver disease, including active HBV infection (HBV DNA >1×10⁴ copies/mL or >2000 IU/mL);
    • Known HCV infection with positive HCV RNA (>1×10³ copies/mL), or other hepatitis, liver cirrhosis;
16. Known brain metastases (except adequately treated, inactive, asymptomatic lesions with no steroid use for at least 30 days);
17. History of allergic reaction to compounds with similar chemical or biological composition to savolitinib;
18. Persistent toxicity from prior anti-tumor therapy not recovered to ≤ Grade 2 (except alopecia and lymphopenia of any grade);
19. Pregnant or breastfeeding women;
20. Received blood transfusion, blood products, or hematopoietic factors (e.g., albumin, G-CSF) within 14 days prior to enrollment;
21. Any clinical or laboratory abnormality or other condition that, in the investigator's opinion, makes the subject unsuitable for participation in this clinical study.

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: Savolitinib plus cetuximab and FOLFOX chemotherapy	Drug: Savolitinib plus cetuximab and FOLFOX chemotherapy; Savolitinib dosing regimen: 200mg, qd, po. Cetuximab: Administered intravenously at an initial dose of 400 mg/m² prior to chemotherapy, followed by a weekly dose of 250 mg/m² infused over 1 hour. FOLFOX chemotherapy regimen: Oxaliplatin 85 mg/m² intravenously over 2 hours on Day 1; leucovorin (LV) 400 mg/m² intravenously over 2 hours on Day 1; 5-FU 400 mg/m² intravenous bolus on Day 1, followed by continuous intravenous infusion of 1200 mg/(m²·day) for 2 days (total dose 2400 mg/m², infused over 46-48 hours).
Active Comparator: Cetuximab plus FOLFOX chemotherapy	Drug: Cetuximab and FOLFOX chemotherapy; Cetuximab: Administered intravenously at an initial dose of 400 mg/m² prior to chemotherapy, followed by a weekly dose of 250 mg/m² infused over 1 hour. FOLFOX chemotherapy regimen: Oxaliplatin 85 mg/m² intravenously over 2 hours on Day 1; leucovorin (LV) 400 mg/m² intravenously over 2 hours on Day 1; 5-FU 400 mg/m² intravenous bolus on Day 1, followed by continuous intravenous infusion of 1200 mg/(m²·day) for 2 days (total dose 2400 mg/m², infused over 46-48 hours).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR)	The incidence of confirmed complete response or partial response	From date of first dose of study drug until disease progression, withdrawal of consent, death, new anticancer therapy (up to approximately 24 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS)	A duration from the date of initial treatment to disease progression or death of any cause. PFS was set as a key secondary outcome.	From date of first dose of study drug until disease progression, withdrawal of consent, death, new anticancer therapy (up to approximately 24 months)
Disease control rate (DCR)	Proportion of patients whose tumor volume control (reduced or enlarged) reaches a predetermined value and can maintain a minimum time limit.	From date of first dose of study drug until disease progression, withdrawal of consent, death, new anticancer therapy (up to approximately 24 months)
Duration of response (DOR)	Duration from the first time reported partial response or complete response to the first time of disease progression or death.	From date of first dose of study drug until disease progression, withdrawal of consent, death, new anticancer therapy (up to approximately 24 months)
Time to response (TTR)	A duration from the date of initial treatment to the first time reported partial response.	From date of first dose of study drug until partial response (up to approximately 12 months)
Overall survival (OS)	Duration from the date of initial treatment to the date of death due to any cause	From date of first dose of study drug until withdrawal of consent or death (up to approximately 24 months)
Number and Proportion of patients with treatment-related adverse events as assessed by CTCAE v6.0	Use descriptive statistical analysis to record the number and proportion of patients who experience treatment-related adverse events out of all patients receiving the study drug. The grading of adverse events follows the CTCAE V6.0.	From the date of first dose of study drug to 90 days after the last administration

Collaborators and Investigators

• Sponsor: Fudan University

Study record dates

Study Major Dates

• Study Start (Estimated): June 30, 2026
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): June 30, 2029

Study Registration Dates

• First Submitted: June 2, 2026
• First Submitted That Met QC Criteria: June 28, 2026
• First Posted (Actual): July 6, 2026

Study Record Updates

• Last Update Posted (Actual): July 6, 2026
• Last Update Submitted That Met QC Criteria: June 28, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Colorectal cancer; cetuximab; c-MET; savolitinib
• 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; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Cetuximab; 1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine
• Other Study ID Numbers: HMPL-504-SUMMER-C101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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