Avelumab as Single Agent in Metastatic or Locally Advanced Urothelial Cancer in Patients Unfit for Cisplatin. The ARIES Study

Exclusion Criteria

• •• Has disease that is suitable for local therapy administered with curative intent.
• •* Has received prior treatment with avelumab.
• •* Has received prior therapy with an anti-PD-1 or anti-PD-L1 agent, or with an agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137).
• •* Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v 5.0 Grade ≥ 3).
• •* Has received previous treatment for metastatic or locally advanced urothelial cancer.
• •* Has a known previous or concurrent malignancy that is progressing or requires active treatment and is distinct in primary site or histology from urothelial cancer within 5 years before randomization.
• •Exceptions cervical cancer in situ or basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy. A history of prostate cancer that was identified incidentally following cystoprostatectomy for bladder cancer is acceptable, provided that the following criteria are met:
• •Stage T2N0M0 or lower;
• •Gleason score ≤ 6,
• •PSA undetectable.
• •* Has major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication
• •* Has active cardiac disease, defined as:
• •1. Myocardial infarction or unstable angina pectoris within 6 months of the first date of study therapy.
• •2. History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled with antiarrhythmic medication); history of QT interval prolongation.
• •3. New York Heart Association (NYHA) Class III or greater congestive heart failure, or left ventricular ejection fraction of \< 40%.
• •* Has uncontrolled hypertension (systolic blood pressure \>150 mmHg or diastolic pressure \>90 mmHg despite optimal medical management)
• •* Has arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), pulmonary embolism within the 4 months before start of study medication.
• •* Persisting toxicity related to prior therapy (NCI CTCAE v. 5.0 Grade \> 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable
• •* Active infection higher than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 grade 2 requiring systemic therapy.
• •* Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
• •* Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive).
• •* Has seizure disorder requiring medication.
• •* Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines
• •* Has known symptomatic metastatic central nervous system (CNS) and/or meningeal tumors. Subjects with previously treated brain metastases may partecipate provided they are stable (the patient is \>2 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable - any neurologic symptoms have returned to baseline - with respect to the tumor at the time of study entry). Also, the patient must not be undergoing acute steroid therapy or tapering (chronic steroid therapy is acceptable provided that the dose is stable for 1 month before and after screening radiographic studies). This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
• •* Has a history of organ allograft.
• •* Has evidence or history of bleeding diathesis. Any hemorrhage or bleeding event of CTCAE grade 3 or higher within 4 weeks of start of study medication.
• •* Has non-healing wound, ulcer, or bone fracture.
• •* Has renal failure requiring hemodialysis or peritoneal dialysis.
• •* Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
• •* Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
• •* Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
• •* Dehydration of NCI-CTCAE version 5.0 grade 1 or higher.Prior organ transplantation including allogenic stem-cell transplantation.
• •* Non-healing wound, ulcer, or bone fracture.
• •* Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
• •* Has a history of substance abuse or medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
• •* Has illness or medical conditions that are unstable or could jeopardize the safety of the patient and his or her compliance in the study.
• •* Has interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
• •* Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.