A Phase II Multicenter Study of Chemotherapy Versus Chemotherapy Plus Durvalumab (MEDI 4736) in Patients With Lymph Node Positive Urothelial Carcinoma of the Bladder

Inclusion Criteria:

• Patients must have histological diagnosis of urothelial carcinoma of the bladder andmust meet criteria for stage cTanyN1-3M0 disease via AJCC 8th edition stagingcriteria30

• Patients must provide tissue by agreeing to transurethethral biopsy of the bladderand the lymph node prior to initiating treatment. If patient is unable or unwillingto undergo biopsy at screening and tissue is available, patient may be eligibile perPI discretion.

• Patients must be ≥18 years of age.

• Patients must have pelvic lymph node amenable for biopsy as assessed by treating MDand interventional radiologist.

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.

• Patients must have a life expectancy of at least 12 weeks.

• Patients must have body weight >30 kg.

• Left ventricular ejection fraction ≥ 50%.

• Adequate organ function as defined below:

• Hematological i. Absolute neutrophil count (ANC) ≥ 1,500/mcL. ii. Platelets ≥100,000 / mcL. iii. Hemoglobin ≥9 g/dL

• Renal iv. Creatinine clearance > 50 ml/min as calculated by the Cockgroft Gaultformula as:

1. CLCR = {[(140-age) × weight)]/(72 x SCR) × 0.85 (if female), where CLCR (creatinine clearance) is measured in mL/min, age is expressed in years,weight in kilograms (kg), and SCR (serum creatinine) in mg/dL.

• Hepatic v. Serum total bilirubin ≤1.5xULN OR Direct bilirubin ≤ULN for subjectswith total bilirubin levels >1.5xULN. vi. AST and ALT ≤2.5xULN OR ≤5xULN forsubjects with liver metastases.

• Coagulation vii. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5xULN unless subject is receiving anticoagulant therapy as long as PT or PTTis within therapeutic range of intended use of anticoagulants. viii. ActivatedPartial Thromboplastin Time (aPTT) ≤1.5xULN unless subject is receivinganticoagulant therapy as long as PT or PTT is within therapeutic range ofintended use of anticoagulants.

• Women of child-bearing potential MUST have a negative serum or urine HCG test unlessprior tubal ligation (>/= 1 year before screening), total hysterectomy or menopause (defined as 12 consecutive months of amenorrhea). Patients should not becomepregnant or breastfeed while on this study. Sexually active patients must agree touse dual contraception for the duration of study participation and for 90 days afterreceipt of last drug on active treatment.

• Ability to understand and willingness to sign informed consent from prior toinitiation of the study and any study procedures.

• Willing and able to comply with scheduled visits, treatment plan, laboratory tests,and other study procedures.

Exclusion Criteria:

• Has metastatic disease to lymph nodes outside of the pelvis or to visceral sites asseen on imaging.

• CTCAE v5.0 Grade ≥ 2 neuropathy.

• CTCAE v5.0 Grade ≥ 2 hearing loss.

• New York Heart Association (NYHA) Class III or IV heart failure defined as:

• Class III heart failure is defined as: patients with cardiac disease resultingin marked limitation of physical activity and/or less than ordinary activitycauses fatigue. Patients are comfortable only at rest.

• Unable to carry on any physical activity without discomfort. Symptoms of heartfailure at rest. If any physical activity is undertaken, discomfort increases

• Known active Hepatitis B, Hepatitis C infection (HCV-DNA positive), or HIVinfection.

• Current or prior use of immunosuppressive medication within 28 days before the firstdose of study drug, with the exceptions of intranasal and inhaled corticosteroids orsystemic corticosteroids at physiological doses, which are not to exceed 10 mg/dayof prednisone, or an equivalent corticosteroid. Systemic steroid administrationrequired to manage toxicities arising from chemotherapy and/or immunotherapydelivered as part of the therapy on trial is allowed.

• Prior exposure to any anti-PD-1 or anti-PD-L1 (including durvalumab) antibody.

• Active or prior documented autoimmune disease within the past 2 years. NOTE:Patients with vitiligo, Grave's disease, or psoriasis not requiring systemictreatment (within the past 2 years) are not excluded.

• History of primary immunodeficiency.

• History of allogeneic organ transplant.

• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.Note:

Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.

• Active infection requiring intravenous (IV) antibiotics or other uncontrolledintercurrent illness requiring hospitalization. Minor infections, e.g. periodontalinfection or urinary tract infection (UTI), which may be treated with short-termoral antibiotics are allowed.

• Active infection of tuberculosis, as determined by clinical signs and symptoms.

• Inability to comply with the study and follow-up procedures.

• History of CVA, myocardial infarction or unstable angina within the previous 6months before starting therapy.

• Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhea, or psychiatric illness/socialsituations that would limit compliance with study requirement, substantiallyincrease risk of incurring AEs or compromise the ability of the patient to givewritten informed consent.

• Has a known additional malignancy that is progressing or requires active treatment.

Exceptions include basal cell carcinoma of the skin, organ confined adenocarcinoma of the prostate, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. Patients may not have received systemic cytotoxic chemotherapy within 1 year of study entry.

• History of exposure to immunotherapy for previous malignancy.

• Intra-vesicular therapy within 4 weeks of study entry or those who have notrecovered from adverse effects of such agents administered more than 4 weeksearlier.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to methotrexate, vinblastine, doxorubicin, cisplatin,durvalumab, or any other agents used in the study.

• Pregnant female patients; breastfeeding female patients; and female or male patientsof childbearing potential who are unwilling or unable to use 2 methods ofcontraception for at least 90 days after the last dose of study drugs. Highlyeffective methods of contraception are those that alone or in combination, result ina failure rate of less than 1% per year when used consistently and correctly. Thesemethods include:

• Established use of oral, inserted, or injected or implanted hormonal methods ofcontraception are allowed provided the patient remains on the same treatmentthroughout the entire study and has been using that hormonal contraceptive for anadequate period of time to ensure effectiveness.

• Correctly placed copper containing intrauterine device (IUD).

• Male condom or female condom used with spermicide (i.e. foam, gel, film, cream orsuppository).

• Male sterilization with appropriately confirmed absence of sperm in the postvasectomy ejaculate.

• Bilateral tubal ligation or bilateral oophorectomy