Neoadjuvant MEDI 4736 +/- Tremelimumab in Locally Advanced Renal Cell Carcinoma

Inclusion Criteria:

* Radiographic evidence of renal cell carcinoma (any histologic subtype) without evidence of distant metastatic disease
* Patients must have clinical stage T2b-4 and/or N1, M0 disease
* Written informed consent and any locally-required authorization (e.g., HIPAA)) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Adequate normal organ and marrow function as defined below:

  * Hemoglobin ≥ 8.0 g/dL
  * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (≥ 1500 per mm3)
  * Platelet count ≥ 100 x 109/L (≥100,000 per mm3)
  * 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 the study sponsor.
  * AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal
  * Glomerular filtration rate \> 40ml/min/1.73m2 as estimated by the Cockcroft-Gault formula or creatinine clearance \>50ml/min as determined by 24-hour urine collection:
  * Estimated creatinine clearance (Clcr) in mL/min by the Cockcroft-Gault (C-G): {\[140 - age ( years)\]× weight (kg)}/{72 × serum creatinine (mg / dL)} ×0.85 for female patients
* Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: ≥60 years old and no menses for ≥1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.
* 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). Previous enrollment in the present study.
* Participation in another clinical study with an investigational product during the last 30 days.
* Prior systemic anti-cancer therapy of any kind for RCC, including but not limited to any approved agent or any previous treatment with a PD1 or PD-L1 inhibitor including durvalumab. No previous treatment with immunotherapy for any malignancy including cytokine, anti-tumor vaccine, T-cell activator, co-stimulator or immune checkpoint inhibitor.
* Evidence of metastatic renal cell carcinoma on imaging and/or biopsy. Involvement of regional lymph nodes is permitted.
* Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from an electrocardiogram (ECG) using Fridericia's Correction (QTcF).

  * a. At Screening, a single ECG will be obtained on which QTcF must be \<470 ms. In case of clinically significant ECG abnormalities, including a QTcF value \>470 ms, 2 additional 12-lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm the finding.
* 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.
* Active or prior documented autoimmune disease within the past 2 years.
* Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
* History of primary immunodeficiency
* History of allogeneic organ transplant
* History of hypersensitivity to durvalumab or any excipient
* History of hypersensitivity to tremelimumab or any excipient
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension (defined as \>160/90 mmHg despite medical therapy), unstable angina pectoris (requiring nitrates), cardiac arrhythmia (NOT including controlled atrial fibrillation), active peptic ulcer disease or gastritis, active bleeding diathesis including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C (detectable RNA) 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
* History of leptomeningeal carcinomatosis
* Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab or tremelimumab
* 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

  * Pregnant or breastfeeding women are excluded from this study.
* Subjects with uncontrolled seizures
* Subjects with known HIV, active hepatitis B, or active hepatitis C (detectable RNA). HIV-positive subjects on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with durvalumab and/or tremelimumab. In addition, these subjects are at increased risk of lethal infections when treated with immunosuppressive therapy.
* Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results