Study of Atezolizumab Combined With Split-dose Gemcitabine Plus Cisplatin in Urothelial Carcinoma

Inclusion Criteria

• Male or female subjects ≥ 18 years old.
• Written informed consent approved by the Independent Ethics Committee (IEC), prior to the performance of any trial activities.
• Patients with histologically documented, locally advanced (T4B, any N; or any T, N2-3) or metastatic urothelial carcinoma (M1, Stage IV)*.

*Also termed transitional cell carcinoma (TCC) or Urothelial Cell Carcinoma (UCC) of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra).

• Patients should not be eligible (unfit) for full dose of cisplatin, in the investigator's judgement, based on:

a. Age older than 70 years. b. Eastern Cooperative Oncology Group (ECOG) Performance status (PS) 2 or Karnofsky PS of 60 - 70% (only 15 patients will be included with ECOG 2). c. Measured creatinine clearance (ClCr) > 30 and 1500 per mm

• Platelet count ≥ 100,000 per mm
• Serum bilirubin ≤ 1.5 X institutional upper limit of normal (ULN) unless liver metastases are present, in which case it must be ≤ 2X ULN. This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology); however, they will be allowed only in consultation with their physician.
• Serum transaminases (ALT, AST and GGT) ≤ 2.5X institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 3X ULN.
• No major active bleeding.
• Female subjects of childbearing potential (not surgically sterile or at least 2 years postmenopausal) must provide a negative urine pregnancy test at screening, and use a medically accepted double barrier method of contraception. In addition, they must agree to continue the use of this double barrier method for the duration of the study and for 6 months after participation in the study.
• Males should agree to abstain from sexual intercourse with a female partner or agree to use a double barrier method of contraception (i.e. condom with spermicide, in addition to having their female partner use some contraceptive measures such as oral contraceptive drugs, intrauterine device (IUD) hormonal contraception, or cervical caps), for the duration of the study and for 6 months after participation in the study
• Willingness and ability of patients to comply with the protocol for the duration of the study including undergoing treatment as well as availability for scheduled visits and examinations including follow up.

Exclusion Criteria

• Prior treatment with any immune checkpoint inhibitor therapy (e.g., CTLA4, PD-1, or PD-L1 targeting agent).*
• Presence of active second malignancy and/or prior malignancy in the last 2 years is allowed except for the following:
• adequately treated basal cell or squamous cell skin cancer,
• adequately treated Stage I or II cancer from which the patient is currently in complete remission per investigators' clinical judgment.
• Patient receiving radiation therapy within 4 weeks before inclusion.
• Active or prior documented autoimmune disease within the past 2 years. Note:

Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.

• Active or prior documented inflammatory bowel disease (e.g.., Crohn's disease and ulcerative colitis).
• History of allogeneic organ transplant.
• Subjects having a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 28 days prior to the first dose of trial treatment.
• Current or prior use of immunosuppressive medication within 7 days prior to enrolment, except the following:

a. Intranasal, inhaled, topical steroids, or local steroid injections i. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or equivalent; ii. Steroids as premedication for hypersensitivity reactions

• The subject has uncontrolled, significant intercurrent