PD-1 Antibody Combined With COX Inhibitor in MSI-H/dMMR or High TMB Colorectal Cancer

Study Overview
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Brief Summary
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PD-1(programmed death protein 1)antibody has been to approved in patients with MSI-H/dMMR advanced cancer and has achieved significant efficacy. It is reported that the objective response rate of Pembrolizumab and Nivolumab are 40% and 31.1% in MSI-H/dMMR (microsatellite instability-high/deficiency mismatch repair )colorectal cancer. What's more, most of the patients who had response for PD-1 antibody achieved a long duration of disease control. However, not all patients with MSI-H/dMMR was sensitive to PD-1 antibody despite it is a biomarker for PD-1 antibody treatment. There were about 50-60% of patients with MSI-H/dMMR were insensitive and we don't know why. What's more, it's reported that tumor mutation burden (TMB) may be another biomarker of response to PD-1 therapy. COX (cyclooxygenase)inhibitor has been proved to prevent adenomas in colorectal and it is safe for most of the patients. Preclinical models also showed that COX inhibitor could act with PD-1 antibody in mice and control disease progress. So, this study aims to evaluated efficacy and safety of combination of PD-1 antibody and COX inhibitor in patients with MSI-H/dMMR or high tumor mutation burden colorectal cancer.

Detailed Description
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This is a single arm, phase two study. Eligible patients with advanced MSI-H/dMMR colorectal cancer were assigned to receive BAT1306 plus COX inhibitor. All patients will receive the study regimen every 3 weeks. Chest/abdomen/pelvic CT with IV contrast will be performed to assess clinical response.

Official Title
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PD-1 Antibody Combined With COX Inhibitor in MSI-H/dMMR or High TMB Colorectal Cancer: a Single Arm Phase II Study

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: PD-1 antibody + cox inhibitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent; able to comply with study and/or follow- up procedures; Age:18-75 years old; Histological or cytological documentation of colorectal cancer; Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; There must be documentation by CT scan, MRI, or intraoperative palpation that tumor is unresectable; Have had at least one lines of chemotherapy fail or refuse to receive chemotherapy; Histologically confirmed metastatic or primary colorectal cancer as dMMR/MSI-H or whole exon sequence confirmed tumor mutation burden higher than 1000; Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment: Hemoglobin (Hb) ≥ 90g/ L, absolute neutrophil count (ANC) ≥ 1.5×109/ L, platelet count ≥ 100×109/ L; Total bilirubin ≤ 1.5×the upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 ×ULN; Serum creatinine ≤1.5×the ULN. Exclusion Criteria: Previous treatment with other therapy targeting T-cell costimulation or immune checkpoint pathways; Active, known, or suspected autoimmune disease (except for type 1 diabetes mellitus, residual hypothyroidism due to autoimmune condition requiring only hormone replacement, or conditions not expected to recur in the absence of an external trigger); A previous cancer active within the previous 5 years; Subjects with known allergy to the study drugs or to any of its excipients; Significant cardiovascular disease including unstable angina or myocardial infarction within 6 months before initiating study treatment; Heart failure grade III/IV (NYHA-classification); Patients with active infection within 1 week before enrollment (infection caused by fever above 38 °C); Patients with severe lung disease (interstitial pneumonia, pulmonary fibrosis, severe emphysema); Patients with active gastrointestinal bleeding; Patients with serious complications (intestinal obstruction, renal insufficiency, hepatic insufficiency, cerebrovascular disorders); Psychiatric disease or a history of central nervous system disease that affects clinical treatment; Receive other anti-tumor treatments (including anti-tumor immunotherapy, interventional therapy and intra-serosal injection of anti-tumor drugs) or participate in other interventional clinical trials within two weeks before enrollment; Breast- feeding or pregnant women; Lack of effective contraception; The investigator determined that the patient was not eligible for this clinical trial.

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: PD-1 antibody + cox inhibitor<br>BAT1306 + aspirin(celebrex when there is contraindication to aspirin) on day 1-21 every three weeks | Drug: PD-1 antibody + cox inhibitor<br>* BAT1306 100mg /pembrolizumab 200mg on day 1 + aspirin 200mg oral (celebrex 400mg oral when there is contraindication to aspirin) on day 1-21 every three weeks Contraindication to aspirin : Allergic or intolerance to aspirin; With peptic ulcers; With hemophilia or other bleeding tendencies; Have the gentic disease glucose-6 phosphate dehydrogenase deficiency.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | CR(complete response) + PR (partial response)rate will be assessed according to the RECIST version 1.1 guidelines. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Time measured from the day of treatment to the date of first documented progression, or death from any cause. | 2 years | 
| Overall survival time | Estimated from the date of treatment to death from any cause. | 5 years | 
| disease control rate | CR + PR + SD(stable disease) rate will be assessed according to the RECIST version 1.1 guidelines. | 6 months | 
| Toxicity assessed using the NCI common toxicity criteria, version 4.0. | The grade of toxicity will be assessed using the NCI common toxicity criteria, version 4.0. | 2 years | 
| duration of response | Time measured from the day of first documented PR or CR to the date of first documented progression, or death from any cause. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MSI-H, dMMR, PD-1 antibody, COX inhibitor, tumor mutation burden