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

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.