At least one standard therapy for advanced disease must have preceded.
Nivolumab plus celecoxib associated with low-dose radiation (escalated doses), and either low-dose cyclophosphamide or ipilimumab followed by nivolumab maintenance
Absence of tumor-infiltrating intraepithelial CD8+ T cells by IHC on baseline biopsy
1) To determine the safety and tolerability of the combination of nivolumab, celecoxib and cyclophosphamide or ipilimumab, in association with escalated low-dose radiation therapy administered concomitantly.
2) To identify the MTD or recommended phase Ib dose RT for radio-immunotherapy combination (RP1bD).
3) To further explore in an expansion cohort the safety and tolerability of the combination of low-dose RT at the RP1bD, with celecoxib, low-dose cyclophosphamide or ipilimumab, plus nivolumab.
-No prior radiation therapy in areas of desired radiation
-Patients may have had prior therapy provided a washout period of 4 weeks prior to registration is allowed. Exception: hormone therapy for breast and prostate cancer is allowed to be continued during the study.
-Recovery from any toxic effects of prior registration to ≤ Grade 1 per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03) except fatigue or alopecia.
-For women of childbearing potential (WOCBP: sexually mature women who have not undergone a hysterectomy, have not been naturally post-menopausal for at least 12 consecutive months or have a serum follicle-stimulating hormone (FSH) < 40 Millions International Units (mIU)/ml):
--Agreement to use 2 acceptable methods of contraception during participation in the trial and for 6 months after last study combined treatment and after 5 months of maintenance treatment
--Women must have a negative urine pregnancy test within 7 days before registration. A positive urine test must be confirmed by a serum pregnancy test, or menopausal as per National Comprehensive Cancer Network (NCCN) guidelines.
-For men: agreement to use 2 acceptable methods of effective contraception during participation in the trial and for 7 months after last study treatment (combined or maintenance treatment). Female partners of men who take part in this trial must also use at least one method of effective contraception during the trial and 7 months after last study treatment (combined or maintenance).
Patients with soft tissue sarcoma, glioblastoma, or lymphoma are excluded.
Pregnant or breast-feeding women.
Symptomatic brain or leptomeningeal disease; any brain metastases must be stable for at least 6 months
Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
a) Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible.
Life expectancy of < 12 weeks
Current, recent (within 4 weeks prior to registration), or planned participation in an experimental drug study
New York Heart Association Class II or greater congestive heart failure
History of myocardial infarction or unstable angina within 6 months prior registration
History of stroke or transient ischemic attack within 6 months prior registration
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior registration)
Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
Patients with active peptic or duodenal ulceration (within 4 weeks prior to registration)
Current or recent (within 14 days prior registration) treatment use of dipyramidole, ticlopidine, clopidogrel, cilostazol, prasugrel, or ticagrelor
Current or recent (within 14 days prior registration) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose
Prophylactic anticoagulation for the patency of venous access devices is allowed, provided the activity of the agent results in an International Normalized Ratio (INR) < 1.5 x ULN and aPTT is within normal limits within 2 weeks prior registration.
Prophylactic use of low molecular-weight heparin (e.g., enoxaparin) is allowed.
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins or allergy to biopharmaceuticals produced in Chinese hamster ovary cells
Known hypersensitivity to any component of the Investigational Medicinal Products (IMPs)
History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. The following exceptions are considered:
--Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible for this study.
--Patients with controlled Type I diabetes mellitus on a stable insulin regimen are eligible
-History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), druginduced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest Computerized Tomography (CT) scan. Exception: history of radiation pneumonitis in previous radiation field (fibrosis) is permitted provided that this area does not undergo current low dose irradiation as part of this protocol.
-Severe infections within 4 weeks prior registration including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
-Signs or symptoms of infection within 2 weeks prior registration
-Received therapeutic oral or IV antibiotics within 2 weeks prior registration. Exception: patients receiving routine antibiotic prophylaxis (e.g., to prevent chronic obstructive pulmonary disease exacerbation or for dental extraction) are eligible.
-Prior allogeneic stem cell or solid organ transplant
-Administration of a live, attenuated vaccine within 4 weeks before registration. Exception: influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine within 4 weeks prior registration or at any time during the study.
-Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
-- Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) or physiologic replacement doses (i.e., prednisone 5-7.5 mg/day) for adrenal insufficiency may be enrolled in the study.
--The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed.