Colorectal Cancer
Conditions
Keywords
MSI-H, dMMR, PD-1 antibody, COX inhibitor, tumor mutation burden
Brief 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.
Detailed description
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.
Interventions
DRUGPD-1 antibody + cox inhibitor
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.
Sponsors
Sun Yat-sen University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response rate | 6 months | CR(complete response) + PR (partial response)rate will be assessed according to the RECIST version 1.1 guidelines. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression free survival | 2 years | Time measured from the day of treatment to the date of first documented progression, or death from any cause. |
| Overall survival time | 5 years | Estimated from the date of treatment to death from any cause. |
| disease control rate | 6 months | CR + PR + SD(stable disease) rate will be assessed according to the RECIST version 1.1 guidelines. |
| Toxicity assessed using the NCI common toxicity criteria, version 4.0. | 2 years | The grade of toxicity will be assessed using the NCI common toxicity criteria, version 4.0. |
| duration of response | 2 years | Time measured from the day of first documented PR or CR to the date of first documented progression, or death from any cause. |
Countries
China
Contacts
Primary ContactYanhong Deng, M.D.
Outcome results
None listed