Evaluation of the Efficacy and Safety of Bevacizumab Combined With PD-1 Monoclonal Antibody in Preoperative Neoadjuvant Therapy for MSS Colorectal Cancer With Liver Metastases

Evaluation of the Efficacy and Safety of Bevacizumab Combined With PD-1 Monoclonal Antibody in Preoperative Neoadjuvant Therapy for MSS Colorectal Cancer With Liver Metastases - a Single-center, Single-arm, Open-label Clinical Trail

Evaluation of the Efficacy and Safety of Bevacizumab Combined With PD-1 Monoclonal Antibody in Preoperative Neoadjuvant Therapy for MSS Colorectal Cancer With Liver Metastases - a Single-center, Single-arm, Open-label Clinical Trail.

Study Overview

• Status: Not yet recruiting
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: Bevacizumab Combined With PD-1 Monoclonal Antibody

Detailed Description

In the 2023 Global Cancer Statistics, colorectal cancer remains the third leading cause of cancer-related death in the world. According to the latest China Cancer report, colorectal cancer is the fourth leading cause of cancer-related death in China. More specifically, the incidence and the mortality of colorectal cancer have been increasing year over year. Among newly diagnosed colorectal cancer patients, 20% have distant metastases. The 5-year survival rate for metastatic colorectal cancer (mCRC) is less than 20%. In the latest updated 2023 National Cancer Comprehensive Network (NCCN) Colon Cancer Guidelines, mismatch repair genes/micro satellite state officially became a global classification standard. Patients diagnosed with colorectal cancer must be classified into MSS or MSI-H before treatment, that is, patients are divided into pMMR/MSS and dMMR/MSI-H subtypes after initial examination or clinical management, and then the treatment plan is determined. MSI-H accounts for 15% of all colorectal cancers and is mostly present in patients with early stage tumors. For patients with metastatic colorectal cancer, MSI-H colorectal cancer accounts for only 5% of all patients. Among them, the treatment of immune checkpoint inhibitors in MSI-H patients has become a first-line and neoadjuvant metastatic disease treatment recommendation.

Although clinical trials on the combination of targeted therapy and immunotherapy are increasing, clinical researches and clinical trials of targeted therapy combined immunotherapy, such as bevacizumab combined with PD-1, have not received enough attention and recognition. Currently reports believed that anti-programmed death-1 (PD-1) antibodies have been shown to produce significantly longer progression-free survival with fewer adverse events compared to chemotherapy as a first-line treatment for dMMR metastatic CRC (mCRC). In the simultaneous CRT sequential PD-1 (long range) and TNT simultaneous combined PD-1 (long range) clinical trials, CRT combined with PD-1/PD-L1 showed better near-term efficacy gains (pCR) in patients with locally staged pMMR. Although current researches on neoadjuvant therapy for MSS type bowel cancer is increasingly abundant, especially PD-1 is becoming more and more popular in the treatment of MSS type bowel cancer, the research in the field of neoadjuvant therapy for MSS metastatic colorectal cancer is still not explored. Therefore, our PD-1 combined with bevacizumab in the treatment of MSS type metastatic bowel cancer has greatly research value.

Based on the above reasons, we designed this study to observe the efficacy and safety of the target-free combination therapy regimen of PD-1 combined with bevacizumab for patients with MSS metastatic colorectal cancer, and strive to provide a high-level evidence-based basis for neoadjuvant therapy regimen for patients with MSS metastatic colorectal cancer.

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Yueming Sun, MD,PHD; Phone Number: 02568306026; Email: jssym@vip.sina.com

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Patients with MSS colorectal cancer who have been diagnosed with liver metastases and are physically able to tolerate neoadjuvant chemotherapy.

Description

Inclusion Criteria:

1. Men and women aged 18-75 years old;
2. Histologically or radiographically proven colon or rectal adenocarcinoma with liver metastases；
3. ECOG performance status score of 0 to 2；
4. Clinical staged any T with liver metastases (M+);
5. MSS status;
6. Adequate haematological, hepatic, and renal function: neutrophil count ≥1.5×109 /L; platelet count ≥75×109 /L; serum total bilirubin ≤1.5×upper normal limits (UNL); aspartate aminotransferase ≤2.5×UNL; alanine aminotransferase ≤2.5×UNL; serum creatinine ≤1.5 x UNL.

Exclusion Criteria:

1. MSI status;
2. Colorectal cancer without liver metastases;
3. Relapsed colorectal cancer;
4. Complicated with active bleeding, perforation, or requiring emergency surgery;
5. Previous systemic anticancer therapy for colorectal cancer disease;
6. Any active or history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications;
7. Patients with other active concurrent non-colorectal cancer;
8. Patients with interstitial lung disease, non-infectious pneumonia or uncontrollable systemic diseases (such as: diabetes, hypertension, pulmonary fibrosis and acute pneumonia);
9. Patients with any Grade 2 or above toxicity as classified by the common terminology criteria for adverse events (CTCAE) (version 5.0) (except for anemia, alopecia and skin pigmentation) which is induced by previous treatment and has not subside;
10. Previously received anti-programmed death-1 (PD-1) or its ligand (PD-L1) antibody, anti- cytotoxic T lymphocyte-associated antigen 4 (cytotoxic T-lymphocyte-associated Protein 4, CTLA-4) antibody Women in pregnancy or lactation;
11. Known positive history or positive test for Human Immunodeficiency Virus or Acquired Immunodeficiency Syndrome (AIDS);
12. History of known or suspected allergies to any related drugs used in the trial; Women who are pregnant or nursing.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Bevacizumab Combined With PD-1 Monoclonal Antibody in Preoperative Neoadjuvant Therapy	Drug: Bevacizumab Combined With PD-1 Monoclonal Antibody; Bevacizumab Combined With PD-1 Monoclonal Antibody in Preoperative Neoadjuvant Therapy for MSS colorectal cancer with liver metastases

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cCR	To evaluate whether neoadjuvant Bevacizumab Combined With PD-1 Monoclonal Antibody would significantly improve the Clinical complete response (cCR) proportion in MSS Colorectal Cancer With Liver Metastases	20 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
R0 resection rate	To evaluate whether neoadjuvant Bevacizumab Combined With PD-1 Monoclonal Antibody would significantly improve the R0 resection rate in MSS Colorectal Cancer With Liver Metastases	1 day
pCR proportion	To evaluate whether neoadjuvant Bevacizumab Combined With PD-1 Monoclonal Antibody would significantly improve the pCR proportion in MSS Colorectal Cancer With Liver Metastases	20 weeks
Major pathological response (MPR)	To evaluate whether neoadjuvant Bevacizumab Combined With PD-1 Monoclonal Antibody would significantly improve the Major pathological response proportion in MSS Colorectal Cancer With Liver Metastases	20 weeks
Disease-free survival (DFS) and overall survival (OS)	To evaluate whether neoadjuvant Bevacizumab Combined With PD-1 Monoclonal Antibody would significantly improve the RFS and OS rate in MSS Colorectal Cancer With Liver Metastases	5 years

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital with Nanjing Medical University

Publications and helpful links

General Publications

• Diaz LA Jr, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fourchardiere C, Rivera F, Elez E, Le DT, Yoshino T, Zhong WY, Fogelman D, Marinello P, Andre T; KEYNOTE-177 Investigators. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022 May;23(5):659-670. doi: 10.1016/S1470-2045(22)00197-8. Epub 2022 Apr 12.

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2023
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: November 5, 2023
• First Submitted That Met QC Criteria: November 8, 2023
• First Posted (Estimated): November 9, 2023

Study Record Updates

• Last Update Posted (Estimated): November 9, 2023
• Last Update Submitted That Met QC Criteria: November 8, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antibodies; Bevacizumab; Antibodies, Monoclonal
• Other Study ID Numbers: CRSYM202311

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
• product manufactured in and exported from the U.S.: Yes