Celecoxib for Colon adenocarcinoma

Inclusion criteria

• {"criterion_text":"-Signed written informed consent"}
• {"criterion_text":"-Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to the start of nivolumab"}
• {"criterion_text":"-Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception"}
• {"criterion_text":"-CT-scan must be performed within 28 days prior to registration"}
• {"criterion_text":"-Patients at least 18 years of age"}
• {"criterion_text":"-Non-metastatic adenocarcinoma of the colon (and rectosigmoid considered as nonrectal and not undergoing neoadjuvant treatment)"}
• {"criterion_text":"-dMMR cohorts 3+6: >cT3 and/or N+"}
• {"criterion_text":"-Colonoscopy must be performed after informed consent to obtain study-specific biopsies. If biopsies are not possible, patients cannot be included in the study"}
• {"criterion_text":"-WHO performance status of 0 or 1"}
• {"criterion_text":"-Screening laboratory tests must meet the following criteria and should be obtained within 7 days prior to randomization/registration: WBC > 2.0 x 10^9/L, ANC > 1.5x10^9/L, platelets > 100 x 10^9/L, Hemoglobin > 5.0mmol/L. Transfusion is allowed to obtain an adequate hemoglobin level. Liver function tests: total bilirubin < 1.5 upper limit of normal (ULN) (except for subjects with Gilbert syndrome, who can have total bilirubin <3.0 mg/dL); alkaline phosphatase <2.5 ULN; transaminases (ASAT/ALAT) <3 x ULN; LDH < 2 x ULN"}
• {"criterion_text":"-Creatinine clearance (Cockcroft-Gault) of >40 ml/min"}
• {"criterion_text":"-Women of childbearing potential (WOCBP)* must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug"}

Exclusion criteria

• {"criterion_text":"-Signs of distant metastases on CT-scan and physical examination"}
• {"criterion_text":"-Current pregnancy or breastfeeding"}
• {"criterion_text":"-Clinical obstruction"}
• {"criterion_text":"-Clinical symptoms or radiological suspicion of perforation"}
• {"criterion_text":"-Previous treatment with immune checkpoint inhibitors targeting including but not limited to CTLA-4, PD-1 or PD-L1"}
• {"criterion_text":"-Previous treatment with chemotherapy"}
• {"criterion_text":"-Radiotherapy prior to or planned post-surgery radiotherapy for disease under study"}
• {"criterion_text":"-Active malignancies other than disease under study within 3 years prior to inclusion, except for malignancies with a negligible recurrence rate (e.g. <10% in 5 years)"}
• {"criterion_text":"-History of allergy to study drug components"}
• {"criterion_text":"-History of severe hypersensitivity reaction to any monoclonal antibody"}
• {"criterion_text":"-Intercurrent illnesses, including but not limited to infections, unstable angina pectoris"}
• {"criterion_text":"-Underlying medical conditions that, in the Investigator’s opinion, will make the administration of the study drug hazardous or obscure the interpretation of toxicity determination of adverse events"}
• {"criterion_text":"-Positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection"}
• {"criterion_text":"-Active autoimmune disease or a documented history of autoimmune disease, or other medical conditions requiring systemic steroid or immunosuppressive medications, except for subjects with vitiligo, diabetes mellitus type 1, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis or resolved childhood asthma/atopy not requiring systemic treatment"}
• {"criterion_text":"-Conditions requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease"}
• {"criterion_text":"-Live vaccines in the 4 weeks prior to inclusion"}
• {"criterion_text":"-History of uncontrolled medical or psychiatric illness"}
• {"criterion_text":"-Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule"}

Primary endpoints

• {"endpoint_text":"-Efficacy as measured by major pathologic response rate (≤10% residual viable tumor (RVT))","definition_or_measurement_approach":"Major pathologic response defined as ≤10% residual viable tumor (RVT) assessed on surgical pathology"}

Secondary endpoints

• {"endpoint_text":"-To assess the major pathological response rate (MPR, <10% viable tumor rest) and complete response rate and whether response correlates with DFS","definition_or_measurement_approach":"MPR defined as <10% viable tumor; correlation with disease-free survival (DFS) to be evaluated"}
• {"endpoint_text":"-To find biomarkers and evaluation strategies able to accurately assess complete and nearcomplete responses in order to pursue organ-sparing treatment (omission of surgery) in this patient population in future trials","definition_or_measurement_approach":"Exploratory biomarker discovery and validation using tissue and blood-based assays"}
• {"endpoint_text":"-To expand current exploratory translational analyses","definition_or_measurement_approach":"Expansion of translational analyses (e.g., RNA sequencing, immune profiling)"}
• {"endpoint_text":"-Analysis of immune cell infiltration and the difference with inflamed pMMR tumors pre- and post-treatment: why is there no pathological response in pMMR tumors showing immune activation? And are there any differences between complete and near-complete responders?","definition_or_measurement_approach":"Pre- and post-treatment biopsy analysis of immune cell infiltration and phenotype"}
• {"endpoint_text":"-Primary readout will be the effect of therapy on intratumoral T-cell infiltration, CD4, CD8 infiltration and immune checkpoints upregulation (including but not limited to PDL1 and LAG3 assessment for nivo/rela cohorts) in the time interval pre- and post-treatment in biopsies","definition_or_measurement_approach":"Quantitative and qualitative assessment of T-cell infiltration and immune checkpoint markers in paired biopsies"}
• {"endpoint_text":"-Immunogenic mutational load will be determined by tumor tissue DNA WES. Peripheral blood DNA WES will also be performed and used as a control for somatic mutation sorting (only genes relating to colon cancer and/or immune-related genes, deemed informational for this study, will be assessed)","definition_or_measurement_approach":"Tumor and peripheral blood whole exome sequencing (WES) to determine mutational load"}
• {"endpoint_text":"-Immune suppressive pathways, IFN-y induced gene expression and COX2 induced gene expression changes will be analyzed by use of RNA sequencing on pre- and post-therapy tissue","definition_or_measurement_approach":"RNA sequencing on paired tissue to analyse pathway and gene expression changes"}
• {"endpoint_text":"-Date of relapse, as determined by disease recurrence or disease-related death during follow-up after surgery. Follow-up will be performed according to local and/or national guidelines","definition_or_measurement_approach":"Relapse date determined by clinical/radiological recurrence or disease-related death; follow-up per local/national guidelines"}
• {"endpoint_text":"-Safety, evaluated by the incidence and severity of irAEs, SAEs and the frequency of delays of surgery >2 weeks from the intended date due to treatment related complications (if not a primary objective of the cohort)","definition_or_measurement_approach":"Safety assessed by incidence/severity of immune-related AEs (irAEs), serious adverse events (SAEs), and surgery delay frequency"}
• {"endpoint_text":"-To evaluate health-related quality of life through patient reported outcome measures","definition_or_measurement_approach":"Patient-reported outcome instruments/questionnaires to assess health-related quality of life"}

Netherlands

Earliest CTIS Part Ii Submission Date

22-07-2024

Latest Decision Or Authorization Date

28-10-2025

Processing Time Days

463

Number Of Sites

8

Number Of Participants

353

Primary sponsor

Full Name

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Netherlands