pd-1 antibody combined with cox inhibitor in msi-h/dmmr or high tmb colorectal cancer

Conditions: Colorectal Cancer

Summary: 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.

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.

Eligibility criteria:
inclusion criteria: 1. signed informed consent; able to comply with study and/or follow- up procedures; 2. age:18-75 years old; 3. histological or cytological documentation of colorectal cancer; 4. eastern cooperative oncology group (ecog) performance status of 0 or 1; 5. there must be documentation by ct scan, mri, or intraoperative palpation that tumor is unresectable; 6. have had at least one lines of chemotherapy fail or refuse to receive chemotherapy; 7. histologically confirmed metastatic or primary colorectal cancer as dmmr/msi-h or whole exon sequence confirmed tumor mutation burden higher than 1000; 8. 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: 1. previous treatment with other therapy targeting t-cell costimulation or immune checkpoint pathways; 2. 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); 3. a previous cancer active within the previous 5 years; 4. subjects with known allergy to the study drugs or to any of its excipients; 5. significant cardiovascular disease including unstable angina or myocardial infarction within 6 months before initiating study treatment; 6. heart failure grade iii/iv (nyha-classification); 7. patients with active infection within 1 week before enrollment (infection caused by fever above 38 °c); 8. patients with severe lung disease (interstitial pneumonia, pulmonary fibrosis, severe emphysema); 9. patients with active gastrointestinal bleeding; 10. patients with serious complications (intestinal obstruction, renal insufficiency, hepatic insufficiency, cerebrovascular disorders); 11. psychiatric disease or a history of central nervous system disease that affects clinical treatment; 12. 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; 13. breast- feeding or pregnant women; 14. lack of effective contraception; 15. the investigator determined that the patient was not eligible for this clinical trial.

Keywords: msi-h dmmr pd-1 antibody cox inhibitor tumor mutation burden