mFOLFOX6+Bevacizumab+PD-1 Monoclonal Antibody in Local Advanced MSS CRC

Study Overview
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Brief Summary
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Immunotherapy has achieved significant therapeutic effect in DNA mismatch repair-deficient or microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC). However, for proficient mismatch repair(pMMR)/microsatellite stable(MSS) CRC, the curative effect of PD-1 monoclonal antibody was poor and most of the data came from stage Ⅳ patients with distant metastasis. Among the whole CRC patients, more than eighty-five percent were pMMR/MSS CRC. It would be very inspiring when major CRC patients(pMMR/MSS) could be benefit from immunotherapy. For T4NxM0 CRC patients, R0 resection was difficult to achieve. If the patients could not got R0 resection, which means the tumors were almost destined to recurrent and patients life time were counting down. Whether combined treatment of mFOLFOX6+ Bevacizumab+PD-1 monoclonal antibody could maximize the curative effect was still unknown. This study aims to evaluate the effect and safety of mFOLFOX6+ Bevacizumab+PD-1 monoclonal antibody treatment combinations in patients with local advanced(T4NxM0) pMMR/MSS CRC.

Detailed Description
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Immunotherapy has achieved significant therapeutic effect in DNA mismatch repair-deficient or microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC). MMR expression and MSS status are the important effective factors of immunotherapy. PD-1monocolnal antibody therapy has accessed excellent treatment effect in advanced dMMR/MSI-H CRC and neoadjuvant therapeutic effect in early colon cancer, more than fifty percent of dMMR/MSI-H CRC patients might get pathological complete response(pCR) after PD-1 monoclonal antibody treatment. The treatments had been proved to be safe and the toxicities were controllable. However, for proficient mismatch repair(pMMR)/microsatellite stable(MSS) CRC, the curative effect of PD-1 monoclonal antibody was poor and most of the data came from stage Ⅳ patients with distant metastasis. Among the whole CRC patients, more than eighty-five percent were pMMR/MSS CRC. It would be very inspiring when major CRC patients(pMMR/MSS) could be benefit from immunotherapy. For T4NxM0 CRC patients, R0 resection was difficult to achieve. If the patients could not got R0 resection, which means the tumors were almost destined to recurrent and patients life time were counting down. However, there were no standard conversion of neoadjuvant treatment recommendations for T4NxM0 CRC. Although PD-1 monoclonal antibody alone has poor effect in pMMR/MSS CRC, it seems to be effective in early stage of MSS CRC(Nicole study) or when it was combined with chemotherapy or target therapy. So far, whether combined treatment of mFOLFOX6+ Bevacizumab+PD-1 monoclonal antibody could maximize the curative effect was still unknown. This study aims to evaluate the effect and safety of mFOLFOX6+ Bevacizumab+PD-1 monoclonal antibody treatment combinations in patients with local advanced(T4NxM0) pMMR/MSS CRC.

Official Title
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Safety and Efficacy of mFOLFOX6+ Bevacizumab+PD-1 Monoclonal Antibody Treatment Combinations in Patients With Local Advanced Microsatellite Stability Colorectal Cancer --an Open Label, Multicenter, Prospective Phase Ⅱ Study (BASKETII)

Conditions
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Colorectal Cancer, Immunotherapy

Intervention / Treatment
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* Drug: mFOLFOX6+Bevacizumab+PD-1 monoclonal antibody treatment combinations


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological identified colon and upper rectum adenocarcinoma, Tumor biopsy immunohistochemical (IHC) identified pMMR, including all of the MSH1,MSH2,MSH6 and PMS2 protein expression and diagnosed as proficient mismatch repair(pMMR), or next generation sequencing identified (MSS)； MRI identified tumor inferior margin higher than peritoneal reflection, Clinical staging T4NxM0, with or without positive MRF, with or without positive EMVI, Staging method：all patients undergo chest,abdominal and pelvic enhanced CT, rectal palpation, high resolution MRI examination，positive perienteric lymph node(LN): short diameter ≥10mm LN or LN with typical metastatic shape and MRI character, clinical data should be re-evaluated and judged by center evaluation group when there are contradictory stagings，distant metastasis were excluded by chest and abdominal enhanced CT and pelvic enhanced MRI, No intestinal obstruction symptom，or obstruction relieved after proximal colostomy, No rectal surgery history, No chemotherapy or radiotherapy history, No biopharmaceutical treatment history(such as monoclonal antibody), immunotherapy(such as anti PD-1antibody, anti PD-L1 antibody, anti PD-L2 antibody or anti CTLA-4), or other research drug treatment, Endocrinotherapy history restriction:No informed consent assigned, Exclusion Criteria: Arrhythmia need anti-arrhythmia treatment(except β-blocking agent or Digoxin)，symptomatic coronary heart disease or myocardial ischemia(myocardial infarction within 6 months) or congestive heart-failure (CHF) > NYHA grade II, Severe hypertension not well controlled by drugs, HIV infection history or active phase of chronic Hepatitis B or C(high copies of virus DNA), Active tuberculosis(TB)，accepting anti-TB treatment or anti-TB treatment within 1 year before trial screen, Other active clinical severe infection(NCI-CTC V5.0), Outside pelvic distant metastasis evidences, Dyscrasia, organ dysfunction, Pelvic or abdominal radiotherapy history, Multiple CRC or Multi-primary tumors； Epilepsy need treatments(Steroid or anti-epilepsy therapy), Other malignant tumor history within 5 years, Over abuse of drugs, medical and psychological or social conditions that might interfere patients or evaluation of the study results, Any active autoimmune disease or autoimmune disease history (including but not restricted：interstitial pneumonia, uveitis,enteritis, hepatitis,hypophysitis, nephritis, hyperthyroidism, hypothyroidism, asthma need bronchodilators), Any anti-infection vaccine injection 4 weeks before inclusion , Long-term exposure to immune-suppressor, combination of systemic or topical use of corticosteroids (dose>10mg/day prednisolone or equivalent hormone)； Known or suspicious allergy to any study related drugs, Any unstable state might cause damage to the safety and compliance of patients, Pregnant or breast feeding women who has ability to have children while without contraception, Refuse to sign informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: mFOLFOX6+ Bevacizumab+PD-1 monoclonal antibody treatment combinations<br>mFOLFOX6+ Bevacizumab+PD-1 monoclonal antibody treatment combinations in patients with local advanced microsatellite stability colon and upper rectum cancer | Drug: mFOLFOX6+Bevacizumab+PD-1 monoclonal antibody treatment combinations<br>* mFOLFOX6+ Bevacizumab+PD-1 monoclonal antibody treatment combinations in patients with local advanced microsatellite stability colorectal cancer<br>* Other names: mFOLFOX6+Bevacizumab+Sintilimab treatment combinations;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PCR rate | pathological complete remission rate in T4NxM0 colorectal cancer treated after mFOLFOX6+Bevacizumab+PD-1monoclonal antibody | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence rate of Grade ≥3 PD-1monoclonal antibody-related adverse events | Incidence rate of participants with Grade ≥3 PD-1monoclonal antibody-related adverse events as assessed by CTCAE v4.0 | 1 year | 
| Incidence rate of Grade ≥3 chemotherapy-related adverse events | Incidence rate of participants with Grade ≥3 chemotherapy-related adverse events as assessed by CTCAE v4.0 | 1 year | 
| R0 resection rate | R0 resection rate in participants treated after mFOLFOX6+Bevacizumab+PD-1monoclonal antibody | 1 year | 
| Down-stage rate | Down-stage rate of pathological stage after surgery compared with clinical stage before drug treatment | 1 year | 
| 3 years DFS Rate | 3 years Disease Free Survival Rate | 3 years | 
| 3 years OS Rate | 3 years Overall Survival Rate | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal cancer, pMMR/MSS, PD-1 monoclonal antibody, Bevacizumab, mFOLFOX6