Durvalumab And Radiation Therapy Followed by Adjuvant Durvalumab in Patients With Urothelial Cancer (T2-4 N0-2 M0) of the Bladder

OUTLINE: This is a multi-center study.

The phase Ib study will evaluate the safety of combining durvalumab with RT followed by
adjuvant durvalumab. The phase II study will estimate the Progression Free Survival (PFS) and
Disease Control Rate (DCR) with durvalumab plus RT followed by single agent durvalumab for
patients with UC of bladder.

PHASE Ib INVESTIGATIONAL TREATMENT:

Cohort 1 will consist of up to 6 patients who will receive durvalumab 1500mg 2 doses Q4
weekly with RT to gross disease, 64.8 Gy, 36 fractions on weekdays over about 7 weeks.
Durvalumab will be started on day 1; RT will be started on day 1 or 2.

Three patients will be enrolled initially. If 2 or more patients (out of 3) experience
dose-limiting toxicity (DLT), the combined treatment will be considered unsafe. Otherwise, an
additional 3 patients will be treated at the same dose. If 0 or 1 patient experience DLT, the
dose of durvalumab will be deemed safe for phase 2 part of the study. If, however, 2 or more
patients (out of 6) experience DLT, the combined treatment will be considered unsafe.

Post-concurrent durvalumab and RT, single agent durvalumab will be given1500mg every 4 weeks
(±7 days) for a total period of up to 12 months. Adjuvant durvalumab treatment will be
started 3-4 weeks post completion of durvalumab and RT.

PHASE II INVESTIGATIONAL TREATMENT:

Subjects will receive durvalumab 1500mg 2 doses Q4 weekly with RT to gross disease, 64.8 Gy,
36 fractions on weekdays over about 7 weeks. Durvalumab will start on Day 1. RT to start on
Day 1 or 2.

Post-concurrent durvalumab and RT, single agent durvalumab will be given1500mg every 4 weeks
(±7 days) for a total period of up to 12 months. Adjuvant durvalumab monotherapy will be
started 3-4 weeks post completion of durvalumab and RT.

Life expectancy of >6 months per treating physician.

Adequate organ and marrow function as defined below:

1. Hemoglobin ≥ 9.0 g/dL

2. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (> 1500 per mm^3)

3. Platelet count ≥ 100 x 10^9/L (>100,000 per mm^3)

4. Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not apply
to subjects with confirmed Gilbert's syndrome (persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or
hepatic pathology), who will be allowed only in consultation with their physician.

5. AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver
metastases are present, in which case it must be ≤ 5x ULN.

6. Serum creatinine CL>30 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976)
or by 24-hour urine collection for determination of creatinine clearance:

Inclusion Criteria:

Phase Ib subjects must meet the following inclusion criteria:

- Locally advanced urothelial cancer of bladder with any of the following:

1. T3-4, N0-2 M0, OR Tx N1-2 M0 OR T2 N1-2 M0: Treatment naïve, unresectable, OR
medically unfit for surgery, OR cisplatin ineligible. T3 N0 M0 patients can be
included if they are cisplatin ineligible.

2. Patients who have T3-4, N0-2 M0 OR Tx N1-2 M0 OR T2 N1-2 M0 post-neoadjuvant
chemotherapy who become unresectable OR medically unfit for surgery.

Phase II subjects must meet the following inclusion criteria:

- Locally advanced urothelial cancer of bladder with any of the following:

1. T3-4, N0-2 M0 OR Tx N1-2 M0 OR T2 N1-2 M0: Treatment naïve, unresectable, OR
medically unfit for surgery OR cisplatin ineligible. T3 N0 M0 patients can be
included if they are cisplatin ineligible.

2. T3-4, N0-1 M0 OR Tx N1-2 M0 OR T2 N1-2 M0 patients post-neoadjuvant chemotherapy
who become unresectable OR medically unfit for surgery.

- T2, N0, M0 who are ineligible to get cisplatin based chemotherapy.

All subjects:

- Written informed consent and HIPAA authorization for personal health information,
obtained from the subject prior to performing any protocol-related procedures,
including screening evaluations.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

- Life expectancy of >6 months per treating physician.

- Subjects must have archival tissue available from previous TURBT (preferred) or lymph
node core biopsy within 8 weeks of treatment or be assessed by the treating urologist
to undergo maximal TURBT. The extent of TURBT may vary for each patient and will be
determined by the treating urologist. Further, the treating urologist will decide if
performing the TURBT is clinically appropriate. If the potential subject does not have
tumor amenable to biopsy, there is insufficient tissue for PD-L1 testing or is not
clinically appropriate for TURBT, enrollment must be discussed with the
sponsor-investigator on a case by case basis.

- Histologically proven urothelial carcinoma of bladder with predominant transitional
cell component. Adenocarcinoma, squamous cell differentiation, or other atypical
histology (such as plasmacytoid or sarcomotoid) of the bladder will be allowed on the
study, provided they form <50% of the histology.

- Females of childbearing potential must have a negative urine and serum pregnancy test
within 3 days of study registration.

NOTE: Female subjects are considered of child bearing potential unless they are surgically
sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral
oophorectomy) or they are ≥60 years old and naturally postmenopausal for at least 12
consecutive months.

- Subject is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.

Exclusion Criteria:

- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site).

- Participation in another clinical study with an investigational product within 2 weeks
prior to registration.

- Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab.

- Previous systemic immunotherapy. Previous use of intravesical BCG is acceptable.

- History of another primary malignancy except for:

1. Malignancy treated with curative intent and with no known active disease ≥5 years
before the first dose of study drug and of low potential risk for recurrence.
However adequately treated prostate cancer >3 years ago with no significant
change in PSA for past 6 months can be included. Patients with a history of
prostate cancer must not have any definitive radiation therapy to prostate area.

2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease.

3. Adequately treated carcinoma in situ without evidence of disease e.g., cervical
cancer in situ.

- Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
antibodies, other investigational agent) within14 days prior to the first dose of
study drug (14 days prior to the first dose of study drug for subjects who have
received prior TKIs [e.g., erlotinib, gefitinib and crizotinib] and within 6 weeks for
nitrosourea or mitomycin C).

- Mean QT interval corrected for heart rate (QTc) ≥470 ms on electrocardiogram (ECG)
using Frediricia's Correction.

- Current or prior use of immunosuppressive medication within 28 days before the first
dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
prednisone, or an equivalent corticosteroid.

- Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy. (Subjects
with irreversible toxicity that is not reasonably expected to be exacerbated by the
investigational product may be included (e.g., hearing loss, peripheral neuropathy).

- Any prior Grade ≥3 Immune-mediated adverse event (imAE) while receiving any previous
immunotherapy agent, or any unresolved imAE >Grade 1.

- 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. Patients with h/o completely resolved childhood
asthma or atopy will not be excluded. Patients with well-controlled hypothyroidism on
thyroxine replacement will be eligible as well.

- Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
ulcerative colitis).

- History of and/or confirmed pneumonitis.

- History of primary immunodeficiency.

- History of allogeneic organ transplant.

- History of hypersensitivity to durvalumab or any excipient.

- History of hypersensitivity to the combination or radiation therapy.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active
bleeding diatheses including any subject known to have evidence of acute or chronic
hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric
illness/social situations that would limit compliance with study requirements or
compromise the ability of the subject to give written informed consent.

- Known history of previous clinical diagnosis of tuberculosis.

- Receipt of live attenuated vaccination within 30 days prior to study entry or within
30 days of starting treatment with durvalumab.

Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated
vaccines, and are not allowed.

- Female subjects who are pregnant, breast-feeding or male or female patients of
reproductive potential who are not employing an effective method of birth control. For
this study male or female patients of reproductive potential need to employ two highly
effective and acceptable forms of contraception throughout their participation in the
study and for 90 days after last dose of study drug

- Any condition that, in the opinion of the investigator, would interfere with
evaluation of study treatment or interpretation of patient safety or study results.

- Brain metastases or history of leptomeningeal carcinomatosis.

- Subjects with uncontrolled seizures.

- Previous definitive radiation to pelvic area.