Study of MEDI4736 (Durvalumab) With or Without Tremelimumab Versus Standard of Care Chemotherapy in Urothelial Cancer

This is a randomized, open-label, controlled, multi-center, global Phase III study to
determine the efficacy and safety of MEDI4736 (Durvalumab) monotherapy and MEDI4736
(Durvalumab) in combination with tremelimumab versus SoC (cisplatin + gemcitabine or
carboplatin + gemcitabine doublet) first-line chemotherapy in treatment-naïve patients with
histologically or cytologically documented, unresectable, Stage IV transitional cell
carcinoma (transitional cell and mixed transitional/non-transitional cell histologies) of the
urothelium (including renal pelvis, ureters, urinary bladder, and urethra) and to allow
sufficient flexibility for Investigators and patients to select the agents that reflect their
normal clinical practice and national guidelines. The patients enrolled in the study will be
randomized 1:1:1 to receive treatment with combination therapy, monotherapy, or SoC
(cisplatin + gemcitabine or carboplatin + gemcitabine, based on cisplatin eligibility).
Patients will be treated with MEDI4736 (Durvalumab) or MEDI4736 (Durvalumab) with
tremelimumab, or treated with SoC until progressive disease (PD) is confirmed, unacceptable
toxicity occurs, withdrawal of consent, or another discontinuation criterion is met. Patients
will be followed for up to 2 years.

Inclusion Criteria:

- Patients with histologically or cytologically documented, unresectable, Stage IV
transitional cell carcinoma of the urothelium who have not been previously treated
with first-line chemotherapy.

- Patients eligible or ineligible for cisplatin-based chemotherapy. Cisplatin
ineligibility is defined as meeting 1 of the following criteria: • Creatinine
clearance (calculated or measured) <60 mL/min calculated by Cockcroft-Gault equation
(using actual body weight) or by measured 24-hour urine collection for determination •
Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 audiometric hearing
loss • CTCAE Grade ≥2 peripheral neuropathy • New York Heart Association ≥Class III
heart failure.

- Tumor PD-L1 status, with Immunohistochemical (IHC) assay confirmed by a reference
laboratory, must be known prior to randomization.

Exclusion Criteria:

- Prior exposure to immune-mediated therapy, including but not limited to, other anti
cytotoxic T-lymphocyte-associated protein 4 (CTLA 4), anti-PD-1, anti-PD-L1, or
anti-PD-L2 antibodies, including therapeutic anticancer vaccines. Prior local
intervesical chemotherapy or immunotherapy is allowed if completed at least 28 days
prior to the initiation of study treatment.

- History of allogenic organ transplantation that requires use of immunosuppressive
agents.

- Active or prior documented autoimmune or inflammatory disorders. The following are
exceptions to this criterion: • Patients with vitiligo or alopecia • Patients with
hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement • Any
chronic skin condition that does not require systemic therapy • Patients without
active disease in the last 3 years may be included but only after consultation with
AstraZeneca • Patients with celiac disease controlled by diet alone may be included
but only after consultation with AstraZeneca.

- Brain metastases or spinal cord compression unless the patient's condition is stable
and off steroids for at least 14 days prior to the start of study treatment. Patients
with suspected or known brain metastases at screening should have an MRI
(preferred)/CT, preferably with IV contrast to access baseline disease status.

- Active infection including tuberculosis, hepatitis B, hepatitis C, or human
immunodeficiency virus (HIV).

- Current or prior use of immunosuppressive medication within 14 days before the first
dose of investigational product (IP). The following are exceptions to this criterion:
• Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra
articular injection) • Systemic corticosteroids at physiologic doses not to exceed 10
mg/day of prednisone or its equivalent • Steroids as premedication for
hypersensitivity reactions (eg, CT scan premedication).

- Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
Patients, if enrolled, should not receive live vaccine during the study and up to 30
days after the last dose of IP.