hARnessing CAbozantinib and Durvalumab Immuno-oncology Association: ARCADIA Study"

Inclusion Criteria:

• Written informed consent.
• Age ≥18 years.
• Body weight >30kg
• Histologically-confirmed diagnosis of UC or variant histologies (e.g. squamous cellcarcinoma, adenocarcinoma, micropapillary tumors, BUT excluding pure small cellcarcinoma) of the bladder or the urothelium.
• Either bladder, urethral, or upper tract primary tumor will be allowed.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Life expectancy of at ≥ 12 weeks.
• Availability of tumor tissue for PD-L1 IHC assay.
• Measurable and non-measurable disease will be included (e.g. patients with bonemetastases only will be allowed for inclusion).
• Failure of 1 or 2 cisplatin-based conventional chemotherapy regimens for metastaticdisease (2nd-to-3rd line only).
• Neoadjuvant/adjuvant regimens will be counted provided that a relapse occurred with 6months of the last cycle of chemotherapy.
• Adequate function of the organs:

1. Absolute neutrophil count (ANC) ≥ 1500/mm3
2. Platelets ≥ 100,000/mm3
3. Hemoglobin ≥ 9 g/dL (≥ 90 g/L).
4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 × upperlimit of normal.
5. Total bilirubin ≤ 1.5 × the upper limit of normal. For subjects with Gilbert'sdisease ≤ 3 mg/dL g. Serum creatinine ≤ 2.0 × upper limit of normal or calculated creatinine clearance ≥ 30 mL/min using the Cockroft-Gault equation h. Lipase < 2.0 times the upper limit ofnormal (ULN)

• Recovery to baseline or ≤ Grade 1 Common Terminology Criteria for Adverse Events (CTCAE) v5.0 from toxicities related to any prior treatments, unless AE(s) areclinically nonsignificant and/or stable on supportive therapy
• Ability to swallow tablets
• Contraception for sexually active fertile patients and their partners. Of note, abarrier method is recommended in addition to the use of steroid hormonalcontraceptives, because the effects of cabozantinib on the pharmacokinetics of thelatter are unknown.
• Evidence of post menopausal status or serum pregnancy test for female pre-menopausalsubject

Exclusion Criteria:

• Patients taking regular oral steroids, above the allowed limit of 10mg/daymethylprednisolone or analogues, for any reason. Patients must not have had steroidsfor 28 days prior to study entry.
• Malignancies other than bladder carcinoma within 5 years prior to Cycle 1, Day 1, withthe exception of those with a negligible risk of metastasis or death and treated withexpected curative outcome (such as adequately treated carcinoma in situ of the cervix,basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgicallywith curative intent) or localized prostate cancer treated with curative intent andabsence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score ≤ 3 + 4 and PSA < 10 ng/mL undergoing active surveillance and treatmentnaive).
• Evidence of significant uncontrolled concomitant disease that could affect compliancewith the protocol or interpretation of results.
• Active or untreated CNS metastases as determined by computed tomography (CT) ormagnetic resonance imaging evaluation during screening and prior radiographicassessments.
• Patients with treated asymptomatic CNS metastases are eligible, provided they meet allof the following criteria:

1. Evaluable or measurable disease outside the CNS
2. No metastases to midbrain, pons, medulla, or within 10 mm of the optic apparatus (optic nerves and chiasm)
3. No history of intracranial or spinal cord hemorrhage
4. No ongoing requirement for corticosteroid as therapy for CNS disease;anti-convulsants at a stable dose are allowed
5. No evidence of significant vasogenic edema
6. No stereotactic radiation, whole-brain radiation or neurosurgical resectionwithin 4 weeks prior to Cycle 1, Day 1
7. Radiographic demonstration of interim stability (i.e., no progression) betweenthe completion of CNS-directed therapy and the screening radiographic study
8. Screening CNS radiographic study ≥ 4 weeks since completion of radiotherapy orsurgical resection and ≥ 2 weeks since discontinuation of corticosteroids

• Pregnant female patients. All female patients of childbearing potential with apositive pregnancy test within 2 weeks prior to the first dose of study treatment willbe excluded from the study.
• Clinically significant cardiovascular disease, for example, myocardial infarction (within 3months prior to enrolment), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure or serious cardiac arrhythmiarequiring medication (beta-blockers and digoxin are allowed)
• Uncontrolled hypertension, stroke or other ischemic or thromboembolic event (DVT, PE)within 6 months before first dose of cabozantinib.
• Severe infections within 4 weeks prior to enrolment in the study including but notlimited to hospitalization for complications of infection, bacteraemia, or severepneumonia.
• Major surgical procedure within 4 weeks prior to enrolmentor anticipation of need fora major surgical procedure during the course of the study other than for diagnosis.Complete wound healing from major surgery must have occurred 1 month before inclusionand from minor surgery (eg, simple excision, tooth extraction) at least 10 days beforeinclusion. Subjects with clinically relevant ongoing complications from prior surgeryare not eligible.
• Received therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior toenrolment (patients receiving prophylactic antibiotics, e.g., for prevention of aurinary tract infection or chronic obstructive pulmonary disease, are eligible).
• Concomitant anticoagulation with oral anticoagulants or platelet inhibitors.
• 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 antiphospholipidsyndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,multiple sclerosis, vasculitis, or glomerulonephritis.
• Patients with a history of autoimmune-related hypothyroidism, unless on a stable doseof thyroid-replacement hormone.
• Patients with uncontrolled Type 1 diabetes mellitus
• Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or correctedserum calcium > ULN) or symptomatic hypercalcemia requiring continued use ofbisphosphonate therapy or denosumab. Patients who are receiving bisphosphonate therapyor denosumab specifically to prevent skeletal events and who do not have a history ofclinically significant hypercalcemia are eligible. Patients who are receivingdenosumab prior to enrollment must be willing and eligible to receive a bisphosphonateinstead while on study.
• radiation therapy for bone within 2 weeks or other radiation therapy within 4 weeksbefore first dose of study treatment. patients with clinically relevant ongoingcomplications from prior radiation therapy
• serious non healing wound/ulcer/bone fracture, moderate to severe hepatic impairment (Child Pugh B or C)
• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-inducedpneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenicorganizing pneumonia), or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field (fibrosis) is permitted).
• Patients with tumors invading major pulmonary vessels and/or with cavitating pulmonarylesions.
• Positive test for HIV.
• Patients with active hepatitis infection (defined as having a positive hepatitis Bsurface antigen [HBsAg] test at screening) or hepatitis C. Patients with pasthepatitis B virus (HBV) infection or resolved HBV infection (defined as having anegative HBs Ag test and a positive antibody to hepatitis B core antigen [anti-HBc]antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibodyare eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
• Patients with active tuberculosis.
• Gastrointestinal disorders likely to interfere with absorption of the study drug (e.g.partial bowel obstruction or malabsorption).
• Subjects with gastrointestinal disorders associated with a high risk of perforation orfistula formation
• Subjects with active peptic ulcer or with a history of clinically significant GIbleeding within 12 weeks before the first dose of study treatment
• Prior treatment with CD137 agonists, anti-PD-1, or anti-PD-L1 therapeutic antibody orpathway-targeting agents.
• Administration of a live, attenuated vaccine within 4 weeks prior to enrolment oranticipation that such a live, attenuated vaccine will be required during the study.
• Treatment with any other investigational agent or participation in another clinicaltrial with therapeutic intent within 28 days prior to enrolment.
• Treatment with systemic immunostimulatory agents (including but not limited tointerferons or interleukin [IL]-2) within 4 weeks or five half-lives of the drug,whichever is shorter, prior to enrolment.
• Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency orglucose-galactose malabsorption