Celecoxib with durvalumab and tremelimumab for advanced liver cancer

Inclusion Criteria:

* Histologically or cytologically confirmed hepatocellular cancer (HCC) planned for treatment at gastrointestinal clinics of Emory University's Winship Cancer Institute or Grady Cancer Center
* Radiologically measurable disease based on Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1
* Age ≥ 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
* Platelet count \> 100,000 cells/ ul (within 28 days of cycle 1 day 1, at the discretion of the investigator)
* Hemoglobin (Hb) \> 9g/dl (within 28 days of cycle 1 day 1, at the discretion of the investigator)
* Absolute neutrophil count \> 1000 cells/dl (within 28 days of cycle 1 day 1, at the discretion of the investigator)
* Albumin \> 3g/dl (within 28 days of cycle 1 day 1, at the discretion of the investigator)
* Total bilirubin \< 3mg/dl (within 28 days of cycle 1 day 1, at the discretion of the investigator)
* Glomerular filtration rate (GFR) \> 60ml/min (based on creatine, and cystatin C estimation where applicable) (within 28 days of cycle 1 day 1, at the discretion of the investigator)
* Females of child-bearing potential (FCBP) must have a negative serum or urine pregnancy test prior to starting therapy
* FCBP and men treated or enrolled on this protocol must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 3 months after completion of study drug administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

  \* A female of childbearing potential (FCBP) is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
* Completion of all previous cancer directed therapy (including, radiotherapy, liver lesion ablation, bland or chemoembolization and transarterial radioembolization therapy) ≥ 4 weeks before the start of study therapy.
* Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class IIB or better.

  * Patients without existing cardiac disease that could raise the risk of complications who consent for the trial will proceed with trial participation
  * Patients with existing cardiac disease that could raise the risk of complications will be referred at the discretion of the investigator to a cardio-oncologist or general cardiologist for cardiac optimization prior to starting celecoxib
* Life expectancy \> 12 weeks as determined by the investigator
* Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol-specified laboratory tests, other study procedures, and study restrictions. This includes willingness to undergo mandatory blood sample draws for evaluation of correlatives
* Evidence of a personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential risks and discomforts, potential benefits, and other pertinent aspects of study participation.

Exclusion Criteria:

* Mild to moderate liver dysfunction evidenced by Child Pugh score 7B and above
* History of arterial or venous thromboembolic events or gastrointestinal bleeding event. Subjects with portal venous thrombosis are permitted in the study if their treating oncologist does not deem it necessary to treat this with heparin products or direct acting anticoagulant (DOAC)
* Current use of warfarin, heparin products and DOACs
* Subjects with a history of (non-bleeding) peptic ulcer disease who have been on a proton pump inhibitor for less than 30 days prior to screening visit
* Patients who have had immune checkpoint inhibitors (ICI) therapy within 6 months prior to entering the study or those who have not recovered from adverse events due to liver directed therapy administered more than 4 weeks earlier (i.e., have residual toxicities \> grade 2)
* Patients who are receiving any other investigational agents or an investigational device within 28 days before administration of first dose of study drugs
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to the agents used in study
* Contraindication to ICI per investigator discretion
* Uncontrolled current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Significant cardiovascular disease (e.g., myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism) within 3 months prior to start of study therapy; angina requiring therapy; symptomatic peripheral vascular disease; New York Heart Association Class 3 or 4 congestive heart failure; or uncontrolled grade ≥ 3 hypertension (diastolic blood pressure ≥ 100 mmHg or systolic blood pressure ≥ 160 mmHg) despite antihypertensive therapy
* Contraindication to non-steroidal anti-inflammatory drugs (NSAIDs): cardiac conditions that significantly raise the risk of cardiopulmonary complications, including unstable angina, uncontrolled heart failure, recent gastrointestinal (GI) bleed. Note that patients who are stable on low dose aspirin (\< 325mg/day) only will be allowed on study
* Current use of other NSAIDs.