Third-line fruquintinib plus serplulimab for advanced metastatic colorectal cancer without liver-only metastases

A Study to Explore the Third-line Treatment of Fruquintinib Combined With Serplulimab in Advanced Non-liver-limited Metastatic Colorectal Cancer: a Single-center, Phase 2 Study

This tests whether combining fruquintinib and serplulimab helps people with microsatellite-stable metastatic colorectal cancer who have already failed standard treatments.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Fudan University (Academic / other)
• Drugs / interventions: radiation, serplulimab, fruquintinib, immunotherapy
• Locations: 2 sites (Shanghai, Shanghai Municipality and 1 other locations)
• Trial ID: NCT05954429 on ClinicalTrials.gov

What this trial studies

This single-center Phase 2 trial gives fruquintinib (an oral anti-angiogenic tyrosine kinase inhibitor) together with serplulimab (an anti-PD-1 antibody) to adults with unresectable, microsatellite-stable metastatic colorectal cancer who progressed after standard therapies. Eligible patients have non-liver-limited metastases and adequate performance status, and treatment continues until disease progression or unacceptable toxicity with imaging assessments by RECIST 1.1. The study collects safety and efficacy endpoints (response rate, progression-free survival, overall survival) and performs extensive biomarker analysis including ctDNA, TPS, CPS, tumor mutation burden, lymphocyte subsets, cytokines, TCR profiling, and gut microbiome. Biomarkers will be correlated with outcomes to help identify which patients are most likely to benefit and potential mechanisms of resistance.

Who should consider this trial

Good fit: Adults (≥18) with histologically confirmed unresectable metastatic colorectal cancer that is microsatellite-stable/pMMR, with non-liver-limited metastases, ECOG 0-2, adequate organ function, and prior progression on standard chemotherapy regimens (fluorouracil, oxaliplatin, irinotecan) and guideline-based targeted therapies.

Not a fit: Patients with liver-limited metastases only, MSI-high/dMMR tumors, those who have not received standard prior therapies, or those with poor performance status or significant comorbidities are unlikely to benefit or may be ineligible.

Why it matters

Potential benefit: If successful, the combination could provide a new third-line option that prolongs disease control and survival for patients with MSS metastatic colorectal cancer.

How similar studies have performed: Early-phase studies combining fruquintinib or other anti-angiogenic agents with PD-1 inhibitors have shown preliminary activity in colorectal cancer, but clear, consistent benefit in microsatellite-stable mCRC has not yet been confirmed.

Eligibility criteria

Inclusion Criteria:

* Age ≥18 years old, both sexes;
* Patients with histologically or cytologically confirmed unresectable and metastatic CRC
* non-liver-limited metastasis: including no liver metastasis or liver metastasis accompanied by other metastatic lesions, such as lung metastasis, peritoneal metastasis, etc
* Before enrollment, the tumor tissue was pMMR by immunohistochemistry, or MSS or MSI-L by PCR or NGS;
* Have received standard treatment in the past and developed disease progression or intolerance to standard treatment based on RECIST 1.1 during or after standard treatment. Standard treatment should include:

  1. Fluorouracil, oxaliplatin and irinotecan
  2. With or without anti-VEGF monoclonal antibody
  3. For RAS wild-type patients, combined with anti-EGFR monoclonal antibody
  4. For patients with BRAF mutations, BRAF inhibitor therapy is recommended when drugs are available
* Patients with ECOG score of 0-2 and expected survival time ≥3 months, patients who can cooperate to observe adverse reactions and efficacy;
* At least one measurable tumor lesion according to RECIST 1.1 criteria
* Good organ function:

  1. neutrophil ≥1.5\*109/L; Platelet ≥100\*109/L; Hemoglobin ≥9g/dl; Serum albumin ≥3g/dl;
  2. Thyroid stimulating hormone (TSH) ≤ 1 times the upper limit of normal, T3 and T4 in the normal range;
  3. bilirubin ≤ 1.5 times the upper limit of normal value; ALT and AST≤ 2 times the upper limit of normal;
  4. Serum creatinine ≤ 1.5 times the upper limit of normal, creatinine clearance ≥60ml/min;
  5. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 times the upper limit of the normal range, unless the patient is receiving anticoagulant therapy and the PT value is within the intended range for anticoagulant therapy;
  6. Activated partial thromboplastin time (aPTT) ≤ 1.5 times the upper limit of normal;
* There were no serious concomitant diseases that could make the survival time less than 5 years;
* Negative pregnancy test in female subjects (for female patients of childbearing potential); Infertile female patients;
* Male patients of childbearing potential and female patients of childbearing potential and at risk of pregnancy must agree to use adequate contraception for the entire duration of the study and for 12 months after receiving treatment with the protocol;
* Signed and dated informed consent indicating that the patient has been informed about all relevant aspects of the study;
* Patients who are willing and able to comply with the visit schedule, treatment plan, laboratory tests, and other study procedures;
* Willing to comply with the arrangement during the study period can not participate in any other clinical research on drugs and medical devices

Exclusion Criteria:

* Pathological diagnosis of other intestinal tumors, such as gastrointestinal stromal tumor;
* Tumor tissues were dMMR detected by immunohistochemistry, or MSI-H detected by PCR or NGS
* Prior treatment with PD-1 antibody, PD-L1 antibody, or CTLA-4 antibody;
* Previous or concurrent history of other malignant tumors, excluding adequately treated non-melanoma skin cancer, cervical carcinoma in situ and thyroid papillary carcinoma;
* Active autoimmune disease, history of autoimmune disease (such as interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism, including but not limited to these diseases or syndromes); It does not include autoimmune-mediated hypothyroidism treated with stable doses of thyroid replacement hormone; Type I diabetes on stable doses of insulin; Vitiligo or cured childhood asthma/allergy without any intervention in adulthood;
* A history of immunodeficiency, including HIV positive, other acquired or congenital immunodeficiency diseases, or organ transplantation or allogeneic bone marrow transplantation;
* Contraindications to antiangiogenic drugs (such as active bleeding, gastrointestinal bleeding, hemoptysis, etc.);
* History of interstitial lung disease (excluding radiation pneumonitis without steroid treatment) and non-infectious pneumonia;
* Patients with active pulmonary tuberculosis infection detected by medical history or CT examination, or with a history of active pulmonary tuberculosis infection within 1 year before enrollment, or with a history of active pulmonary tuberculosis infection more than 1 year before enrollment but without regular treatment;
* The subject has active hepatitis B (HBV DNA ≥2000 IU/mL or 104 copies/mL), hepatitis C (hepatitis C antibody positive and HCV-RNA above the detection limit of the assay)
* Severe cardiopulmonary and renal dysfunction;
* Have hypertension that is not well controlled with antihypertensive medication (systolic blood pressure ≥140mmHg or diastolic blood pressure ≥90mmHg);
* A history of psychotropic substance abuse, alcohol or drug abuse;
* Other factors that may affect subject safety or trial compliance as judged by the investigator. Severe medical conditions requiring concomitant treatment (including mental illness), serious laboratory abnormalities, or other family or social factors

Where this trial is running

Shanghai, Shanghai Municipality and 1 other locations

• Fudan University Shanghai Cancer Center — Shanghai, Shanghai Municipality, China (Not_yet_recruiting)
• Fudan University Shanghai Cancer Center — Shanghai, Shanghai Municipality, China (Recruiting)

Conditions Colorectal Cancer; MSS; serplulimab; fruquintinib