Neoadjuvant Serplulimab & Bevacizumab With FOLFOX vs. FOLFOX Alone in RAS/BRAF WT, pMMR/MSS CRC Patients

Neoadjuvant Combination of Serplulimab and Bevacizumab With FOLFOX Versus FOLFOX Alone for Resectable Liver Metastases in RAS/BRAF Wild-Type, pMMR/MSS Colorectal Cancer Patients

The primary objective of this study is to assess whether the addition of Serplulimab (a PD-1 inhibitor) and Bevacizumab (an anti-angiogenesis agent) to the standard FOLFOX chemotherapy can enhance the immune microenvironment in the liver, increase T lymphocyte infiltration, and consequently improve the postoperative prognosis for patients with surgically resectable colorectal cancer liver metastases (RAS/BRAF wild-type, pMMR/MSS) compared to FOLFOX alone.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; Liver Metastases
• Intervention / Treatment: Drug: Oxaliplatin; Drug: Fluorouracil; Drug: Serplulimab; Drug: Bevacizumab

Detailed Description

In this prospective, multi-center clinical trial titled "INTENSIFY," we seek to evaluate the potential benefits of integrating Serplulimab and Bevacizumab with the standard FOLFOX chemotherapy regimen as neoadjuvant treatment for surgically resectable colorectal cancer liver metastases (CRLM). Colorectal cancer remains a leading cause of global cancer-related morbidity and mortality, with liver metastases accounting for a significant proportion. Our primary objective is to investigate whether the addition of Serplulimab, a PD-1 inhibitor, and Bevacizumab, an anti-angiogenesis agent, can improve the postoperative prognosis for patients with RAS/BRAF wild-type, pMMR/MSS CRLM. We aim to address critical questions regarding the efficacy of this combined treatment in enhancing the immune microenvironment within the liver, ultimately leading to increased T lymphocyte infiltration and improved patient outcomes. The study will involve a randomized assignment of patients to either the standard FOLFOX chemotherapy arm or the experimental arm receiving FOLFOX in combination with Serplulimab and Bevacizumab. Participants will undergo neoadjuvant treatment, surgical resection, and regular follow-up assessments to evaluate treatment response, recurrence rates, and overall survival. By comparing outcomes between the two groups, specifically assessing factors like recurrence-free survival, overall survival, and changes in the immune microenvironment, we aim to provide valuable insights into the optimization of treatment strategies for this specific subset of colorectal cancer patients.

• Study Type: Interventional
• Enrollment (Estimated): 156
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Yuhong Li, PhD; Phone Number: 020 87342487; Email: liyh@sysucc.org.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Recruiting
      • Sun Yat-sen University Cancer Center
      • Contact: Yu-hong Li, MD, Ph D; Email: liyh@sysucc.org.cn
      • Principal Investigator: Yu-hong Li, MD, Ph D

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age ≥18 and ≤75 years old
• Histologically confirmed colorectal adenocarcinoma
• Radiological and/or pathological confirmation of liver metastases, with ≤5 lesions
• Genetic testing and/or immunohistochemistry confirmation of RAS, BRAF wild-type, and pMMR/MSS
• Absence of extrahepatic metastases confirmed by CT, MRI, or PET/CT (if necessary)
• Primary colorectal tumor has been or can be radically resected
• Liver metastatic lesions are resectable (including radiofrequency ablation and SBRT), and postoperative NED (no evidence of disease) is expected. Resectable liver metastases are specifically defined as ① ≤5 metastatic lesions; ② R0 resection can be performed (including radiofrequency ablation and SBRT); ③ Sufficient residual liver volume is expected after resection; ④ At least one hepatic vein can be preserved after resection, with preserved blood flow in and out of the residual liver and preserved bile ducts, and can preserve at least two adjacent liver segments; ⑤ No extrahepatic metastases.
• No prior anti-tumor therapy for liver metastases, except for surgical resection of primary lesions
• Normal hematological function (platelets >90×109/L; white blood cells >3×109/L; neutrophils >1.5×109/L)
• Serum bilirubin ≤1.5 times the upper limit of normal (ULN), transaminases ≤5 times ULN, alkaline phosphatase ≤2.5 ULN, no ascites, normal coagulation function, albumin ≥35g/L
• Liver function classified as Child-Pugh grade A
• Serum creatinine below the upper limit of normal (ULN), or calculated creatinine clearance rate >50ml/min (using Cockcroft-Gault formula)
• ECOG performance status 0-1
• Expected lifespan >3 months
• Signed written informed consent
• Willing and able to be followed up until death or end of study or study termination.

Exclusion Criteria:

• Diagnosis of colorectal cancer with distant extrahepatic metastases
• Prior chemotherapy, targeted therapy, intervention, or immunotherapy for liver metastases
• No planned surgical resection for liver metastatic lesions
• Received oxaliplatin-containing adjuvant chemotherapy regimen within the past one year
• Any toxicity residuals from previous chemotherapy, excluding alopecia, such as peripheral neuropathy ≥NCI CTC v3.0 grade 2
• Use of immunosuppressive drugs one week prior to study treatment initiation, excluding topical corticosteroids via nasal, inhalational, or other routes or physiological doses of systemic corticosteroids (i.e., not exceeding 10 mg/day of prednisone or equivalent) or steroids used for prevention of contrast agent allergy
• Interstitial lung disease requiring corticosteroid treatment
• Known active autoimmune disease requiring symptomatic treatment or with a history of such disease within the past 2 years. Patients with vitiligo, psoriasis, alopecia, or Graves' disease who have not required systemic treatment within the past 2 years, patients with hypothyroidism requiring only thyroid hormone replacement therapy, and patients with type I diabetes requiring only insulin replacement therapy can be included
• Known history of primary immunodeficiency
• Patients with active tuberculosis
• History of allogeneic organ or hematopoietic stem cell transplantation
• Known allergy to any monoclonal antibody or chemotherapy drug (Fluorouracil, oxaliplatin) preparation or excipient component
• Bleeding tendency or coagulation disorder
• Significant symptoms of intestinal obstruction
• Hypertensive crisis or hypertensive encephalopathy
• Severe uncontrolled systemic complications such as infection or diabetes
• Clinically severe cardiovascular diseases such as cerebrovascular accident (within 6 months before enrollment), myocardial infarction (within 6 months before enrollment), hypertension that remains uncontrolled after appropriate drug treatment, unstable angina pectoris, congestive heart failure (NYHA 2-4), or arrhythmia requiring medication
• Past or physical examination showing central nervous system diseases (such as primary brain tumor, epilepsy uncontrolled by standard treatment, any history of brain metastasis, or stroke)
• Diagnosis of other malignant tumors within the past 5 years (excluding basal cell carcinoma and/or carcinoma in situ of the cervix after radical surgery)
• Patients who received any investigational drug therapy within the last 28 days prior to the study
• Pregnant or lactating women and women of childbearing age not using or refusing to use effective non-hormonal contraception (intrauterine devices, barrier contraception combined with spermicidal gel, or sterilization surgery) or men with reproductive potential unwilling or unable to comply with the study protocol

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
Active Comparator: FOLFOX only group; Oxaliplatin: 85 mg/m2 IV on day 1 Fluorouracil (FU): 400 mg/m2 IV bolus on day 1, followed by 2.4 g/m2 continuous IV infusion over 48 hours Leucovorin: 200 mg/m2 IV on day 1 This treatment regimen is repeated every two weeks for a total of 6 cycles.	Drug: Oxaliplatin; 5 mg/m2 IV on day 1; Other Names: Eloxatin; Drug: Fluorouracil; 400 mg/m2 IV bolus on day 1, followed by 2.4 g/m2 continuous IV infusion over 48 hours; Other Names: 5-FU
Experimental: Serplulimab + Bevacizumab + FOLFOX; Serplulimab: 200 mg IV infusion on day 1 Bevacizumab: 5 mg/kg IV infusion on day 1 Oxaliplatin, FU, and Leucovorin as per the control arm The experimental arm follows the same treatment schedule as the standard FOLFOX regimen, with the addition of Serplulimab and Bevacizumab for the first 3 cycles only.	Drug: Oxaliplatin; 5 mg/m2 IV on day 1; Other Names: Eloxatin; Drug: Fluorouracil; 400 mg/m2 IV bolus on day 1, followed by 2.4 g/m2 continuous IV infusion over 48 hours; Other Names: 5-FU; Drug: Serplulimab; 200 mg IV infusion on day 1; Other Names: anti-PD-1 antibody; Drug: Bevacizumab; 5 mg/kg IV infusion on day 1; Other Names: Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3-year Progression-Free Survival Rate	The proportion of patients who, following the initiation of treatment, remain both alive and without evidence of disease progression for a consecutive period of three years.	Assessed for three years following the initiation of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Overall Survival	The duration of time from diagnosis until death	Assessed throughout the study duration (5 years)
Major Pathological Response (MPR)	Defined as residual viable tumor of less than or equal to 10%	Assessed following neoadjuvant treatment and resection of CRLM (up to 5 years)
Pathologic complete response (pCR)	The absence of tumor cells in all specimens.	Assessed following neoadjuvant treatment and resection of CRLM (up to 5 years)
Pathological Partial Response	Defined as residual viable tumor of more than 10% but less than 50%	Assessed following neoadjuvant treatment and resection of CRLM (up to 5 years)
Disease Free Survival	The measure of time after treatment during which no sign of cancer is found	Assessed throughout the study duration (5 years)
Treatment-related adverse events	Assessment of adverse events related to the treatment received in both arms	Assessed throughout the study duration (5 years)

Collaborators and Investigators

• Sponsor: Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: February 20, 2024
• First Submitted That Met QC Criteria: February 20, 2024
• First Posted (Actual): February 28, 2024

Study Record Updates

• Last Update Posted (Estimated): March 4, 2024
• Last Update Submitted That Met QC Criteria: March 1, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Fluorouracil; Oxaliplatin; Bevacizumab
• Other Study ID Numbers: INTENSIFY-CRC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Data and materials used in this study can be made available following study completion upon reasonable request to the corresponding author, subject to ethical and legal considerations and applicable data-sharing agreements.

Drug and device information, study documents

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