Avelumab Plus Carboplatin-gemcitabine in Urothelial Carcinoma

Inclusion Criteria:

1. The patient has given written informed consent stating that he or she understands the purpose of the study and the procedures involved and agrees to participate in the study.
2. The patient has histologically confirmed unresectable UC (T4b, any N; or any T, N2-3) or metastatic (M1, Stage IV) UC of the urinary tract, including renal pelvis, ureters, urinary bladder, and urethra
3. No prior systemic therapy for inoperable locally advanced or metastatic UC. For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo radiation for UC, a treatment-free interval \>12 months between the last treatment administration and the date of recurrence is required in order to be considered treatment naive in the metastatic setting.
4. Ineligible ("unfit") for cisplatin-based chemotherapy as defined by any one of the following criteria:

   1. Impaired renal function (GFR \<60 mL/min)
   2. ECOG performance status of 2
   3. Grade ≥2 hearing loss (measured by audiometry) or ≥25 dB at two contiguous frequencies
   4. Grade ≥2 peripheral neuropathy \* Criteria 4a and b are mutually exclusive: those patients with ECOG 2 won't be allowed to have an impaired renal function. For rest of the criteria, several of them may coexist.
5. The patient has at least one measurable tumour lesion (measurable disease, as defined by the RECIST criteria v1.1). If all sites of measurable disease have been irradiated, one site must have demonstrated growth after irradiation.
6. Age ≥18 years.
7. ECOG PS 0-2.
8. Life expectancy of at least 12 weeks.
9. Adequate hematologic, hepatic, and renal function, defined by:

   1. Platelet count ≥100 x10\^9/L.
   2. Hemoglobin ≥ 9 g/dL (may have been transfused).
   3. Absolute neutrophil count (ANC) ≥1.5x10\^9/L.
   4. Serum creatinine value not clinically significant; if creatinine \>1.5 times the upper limit of normality (ULN), creatinine clearance will be calculated according to Chronic Kidney Disease Epidemiology group (CKD-EPI) formula or local formula and patients with creatinine clearance \<30 mL/min shall be excluded.

      NOTE: The CKD-EPI formula for creatinine clearance is as follows:

      GFR = 141 x min(Scr/κ,1)\^α x max(Scr/κ,1)\^-1.209 x 0.993\^Age x 1.018 \[if female\] x 1.159 \[if black\].

      Where Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1.
   5. Alanine aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT) and alkaline phosphatase (AP) ≤2.5 ×ULN (≤5 ×ULN in the presence of liver metastasis), unless this AP increase is explained due to the presence of bone metastases (with patient matching ALT, AST and bilirubin criteria), and serum total bilirubin ≤1.5 ×ULN.
10. Archival or newly-obtained representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks must be available.
11. Females of childbearing potential must have a negative serum pregnancy test within 7 days of study entry. Patients of childbearing potential who participate in this study must use effective contraceptive methods (e.g., abstinence, intrauterine device, oral or injectable contraceptives, a double barrier method or surgical sterility) to prevent pregnancy starting as soon as the informed consent form is signed and continuing for at least 13 weeks after the last dose of the study medication is administered.

Exclusion Criteria:

1. Women who are currently pregnant or breast-feeding.
2. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade \> 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable.
3. Patients who had undergone major surgery, radiation therapy or treatment with chemotherapy or any investigational agent within 28 days prior to Study day 1.
4. Evidence of severe or uncontrolled systemic disease or any concurrent condition (including uncontrolled diabetes mellitus) which in the Investigator's opinion makes it undesirable for the subject to participate in the study or which would jeopardize compliance with the protocol.
5. History of another neoplasm. However, patients with prior history of either non-metastatic non melanoma skin cancers; carcinoma in situ of the cervix; or cancer cured by surgery, small field radiation or chemotherapy ≥3 years prior to randomisation; or treated patients with early stage and low risk prostate cancer (≤pT2 N0 M0, Gleason ≤6 and Prostate-specific antigen \[PSA\] ≤0.5 ng/mL) at study entry will be eligible.
6. Prior allogeneic stem cell or solid organ transplantation, or active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. However, patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible
7. Current use of immunosuppressive medication, EXCEPT for the following:

   1. Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection);
   2. Systemic corticosteroids at doses ≤10 mg/day of prednisone or equivalent;
   3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
8. History of pulmonary fibrosis.
9. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (\< 6 months prior to enrolment), myocardial infarction (\< 6 months prior to enrolment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
10. Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
11. 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).
12. Active tuberculosis.
13. Active infection requiring systemic therapy.
14. Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines.
15. Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3).
16. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behaviour; 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.