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

Objectives:

Primary Objective

• To investigate the safety and feasibility of neoadjuvant plus adjuvant dosing of durvalumab
+/- tremelimumab in patients with localized renal cell carcinoma (RCC).

Secondary Objectives

- To assess the immune response to neoadjuvant plus adjuvant dosing of durvalumab +/-
tremelimumab in patients with localized RCC as measured an increased density of
tumor-infiltrating CD8 T-cells.

- To assess the antitumor effect of neoadjuvant durvalumab +/- tremelimumab in patients
with RCC as measured by change in tumor size.

Correlative Objectives

- To explore pharmacodynamic and microbiome markers of response to checkpoint inhibition
in pre- and post-treatment blood and tissue samples (e.g. infiltration of T cells, T
regulatory cells and/or Myeloid-derived suppressor cells).

- To understand changes in the immunological milieu mediated by pre-surgical immune
checkpoint blockade (e.g. change in T cell repertoire, expression of T cell agonist
targets).

Study Design:

This study will be a single-arm open-label phase Ib study of neoadjuvant durvalumab +/-
tremelimumab in localized / locally advanced, non-metastatic RCC patients suitable for
nephrectomy. Upon selection as appropriate for study, patients will undergo computed
tomography (CT)-guided biopsy of renal mass to obtain histological confirmation of diagnosis,
and immunologic characterization of the RCC tumor. Peripheral blood will also be drawn at
time of screening. Patients will subsequently receive systemic neoadjuvant treatment in one
of 5 cohorts as defined below. Following systemic therapy, patients will undergo nephrectomy.
Type of surgery (open vs. minimally invasive, radical vs. partial) and template for lymph
node dissection are at the discretion of surgeon. Timing of surgery in relation to adverse
events and/or treatment for adverse events from neoadjuvant dosing of study drugs is at the
discretion of the surgeon. Adjuvant therapy will be administered within 4-6 weeks of surgery.
Subsequent follow-up will then be completed to assess adverse event resolution and long-term
outcomes.

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