Preoperative Nivolumab Plus Bevacizumab Combined With Chemotherapy Before Surgery in Patients With pMMR/MSS Colorectal Cancer Liver Metastases

Study Overview
=================
Brief Summary
-----------------
This prospective, single-arm study aims to investigate the safety and efficacy of Nivolumab plus bevacizumab and chemotherapy as neoadjuvant treatment in pMMR/MSS Colorectal cancer liver metastases patients

Official Title
-----------------
Safety and Efficacy of Nivolumab Combined With CAPOX Plus Bevacizumab as Neoadjuvant Treatment of pMMR/MSS Colorectal Cancer Liver Metastases Patients：a Single-arm, Phase II, Prospective Study

Conditions
-----------------
Colorectal Cancer Liver Metastases

Intervention / Treatment
-----------------
* Drug: CapOx(Capecitabine+ Oxaliplatin)
* Drug: Bevacizumab
* Drug: Nivolumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥18 years old and ≤75 years old On the basis of data from the literature, we defined liver metastases as B/U if at least one of the following was present: more than four liver metastases, involvement of the hepatic artery or portal vein, or involvement of the biliary duct. A trained radiologist reviewed radiologic images (computed tomography or magnetic resonance imaging scans of the abdomen) taken before the conversion chemotherapy to assess the resectability criteria. Immunohistochemistry and/or genetic testing confirmed pMMR/MSS Initial diagnosed or recurrent patients will be accepted, patients with recurrence should not have received any treatment include chemotherapy, targeted therapy or immunotherapy within 1 month or radiotherapy within 1 year Measurable disease according to the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria and haven't received any local treatment. Eastern Cooperative Oncology Group (ECOG) 0-1. Absence of distant metastasis confirmed by CT, MRI or PET/CT Adequate hematologic and organ function, defined by protocol-specified laboratory test results, obtained within 7 days before first dose. Absolute neutrophil count ≥1500/mm3, platelet ≥100,000/mm3, Hb ≥10g/dl, serum creatinine ≤1.5 times ULN, creatinine clearance rate ≥50mL/min, ALT and AST ≤2.5 times ULN, INR or aPTT ≤1.5 times ULN (INR ≤2 times ULN and aPTT in normal range for patients who are on prophylactic anticoagulant therapy within 14 days before study treatment), total bilirubin level ≤2 times ULN (within 7 days before study treatment). Women of childbearing age should confirm that serum pregnancy test is negative and agree to use effective contraceptive methods during study treatment and the following 60 days. Life expectancy> 3 months Signed and written informed consent Exclusion Criteria: Previously received anti-PD1 or anti-PDL1 or anti-PDL2 or anti-CTLA4. Uncontrolled active bleeding from the primary tumor or intestinal obstruction. Contraindications of bevacizumab Hypersensitivity to other monoclonal antibodies. Any active, known or suspected autoimmune disease. Uncontrolled pleural effusion, pericardial effusion, or ascites to a moderate or greater extent. History of one of the following diseases: idiopathic pulmonary fibrosis, organized pneumonia (eg. bronchiolitis obliterans), drug-induced pneumonia, idiopathic pneumonia and interstitial pneumonia, or evidence of active pneumonia through enhanced chest CT screening. Major surgery within 4 weeks before enrollment and haven't fully recovered from the previous surgery. Active bleeding or abnormal coagulation (aPTT >43s or INR >1.5 times ULN), or having a tendency to bleed or receiving thrombolytic or anticoagulant therapy. Previously received allogeneic stem cell or parenchymal organ transplantation. Any significant clinical or laboratory abnormality that the investigator considers to influence the safety assessment, eg. uncontrolled active infection, uncontrolled diabetes, hypertension that cannot be reduced to normal range with monotherapy, grade II or above peripheral neuropathy, congestive heart failure, heart disease (class II or higher) as defined by the New York College of Cardiology, myocardial infarction within 3 months prior to enrollment, unstable arrhythmias, unstable angina pectinis, chronic kidney disease, abnormal thyroid function and previous or co-existing malignancies. History of uncorrected serum electrolyte disturbances such as potassium, calcium and magnesium. HIV infection. Active hepatitis B or hepatitis C. Pregnancy or lactation period, or unwilling to use contraception during the trial. With other malignancy within 5 year, except cervical carcinoma in situ, basal or squamous skin cancer, local prostatic carcinoma and ductal carcinoma in situ. Use corticosteroids (dose of prednisone or similar drugs> 10mg/day) or other immunosuppressive agents within 14 days before enrollment. Patients with active tuberculosis (TB) who are receiving anti-TB treatment or have received anti-TB treatment within 1 year. Active infection, or treatment with oral or intravenous antibiotics within the first 2 weeks prior to neoadjuvant therapy, except prophylactic administration. Anti-infective vaccine (eg. influenza vaccine, varicella vaccine, etc.) injection within 4 weeks before neoadjuvant therapy. Previous participation in other clinical trials within 4 weeks before neoadjuvant therapy. Any other disease, metabolic disorder, abnormal physical examination or abnormal laboratory results that may contrain the use of trial drug, or affect the reliability of study results, or lead to high risk of treatment complications, or affect patient compliance.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab + Bevacizumab + CAPOX as neoadjuvant treatment for 4 cycles<br>CapOx: Capecitabine is given orally at 1500mg / m² twice a day from day1-14 every 3 weeks for 4 cycles and Oxaliplatin is given by intravenous infusion at 200mg / m2 on Day 1 every 3 weeks for 4 cycles; Bevacizumab：Bevacizumab is given intravenously at 10mg/kg on day 1 every 3 weeks for 4 cycles; Nivolumab：Nivolumab is given intravenously at 360 mg on day 1 every 3 weeks for 4 cycles; | Drug: CapOx(Capecitabine+ Oxaliplatin)<br>* CapOx: Capecitabine is given orally at 1500mg / m² twice a day from day1-14 every 3 weeks for 4 cycles and Oxaliplatin is given by intravenous infusion at 200mg / m2 on Day 1 every 3 weeks for 4 cycles<br>Drug: Bevacizumab<br>* Bevacizumab is given intravenously at 10mg/kg on day 1 every 3 weeks for 4 cycles<br>Drug: Nivolumab<br>* Nivolumab is given intravenously at 360 mg on day 1 every 3 weeks for 4 cycles<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| R0 recession rate | Percentage of patients who achieve R0 resection | 10 weeks | 
| Pathological complete response rate | Percentage of patients who achieve pathological complete response (pCR) based on local investigator | 15 weeks | 
| Tumor regression grade (TRG） |  | 15 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | Percentage of patients who achieve partial response (PR) or complete response (CR) based on Response Evaluation Criteria In Solid Tumors (RECIST). | Up to 3 years | 
| Event free survival | Measure of time from study treatment to disease progression or death. | Up to 3 years | 
| Disease-free surviva | Measure of time from the date of surgery to disease relapse or death. | Up to 3 years | 
| One-year or two-year disease-free survival rate | Percentage of patients who achieve disease-free survival lasting for more than one and two years respectively from the date of surgery. | Up to 2 years | 
| One-year or two-year overall survival rate | Percentage of patients who achieve survival for more than one and two years respectively from date of first dose. | Up to 2 years | 
| Incidence of Treatment-Related Adverse Events | Number of adverse events | Until 30 days after the last treatment | 
| Quality of life score (QoL score） | Assessment of life quality based on EORTC QLQ-C30 | Until 30 days after the last treatment |