Study of Nivolumab and Axitinib in Patients With Advanced Renal Cell Carcinoma

Inclusion Criteria:

- Histologically or cytologically confirmed advanced RCC with predominantly clear cell
subtype.

- Archival tumor biospecimen (when available) must be procured for correlative
evaluation. If tumor tissue is not available or accessible despite good faith efforts,
patient may still be treated on study.

- Formalin fixed, paraffin embedded [FFPE] tissue block(s) or at least 12 unbaked,
unstained slides are required. Tissue samples taken from a metastatic lesion prior to
the start of screening are acceptable.

- At least one measureable lesion as defined by RECIST version 1.1.

- Age > 18 years.

- ECOG performance status 0 or 1

- Adequate bone marrow, kidney, and liver function as defined by: WBC ≥ 2000/μL.
Neutrophils ≥ 1500/μL. Platelets ≥ 100 x103/μL. Hemoglobin > 9.0 g/dL. Serum
creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the
Cockcroft-Gault formula): Female CrCl = (140 - age in years) x (weight in kg x
0.85)/(72 x serum creatinine in mg/dL). Male CrCl = (140 - age in years) x (weight in
kg x 1.00)/(72 x serum creatinine in mg/dL). AST/ALT ≤ 3 x ULN. Total Bilirubin ≤ 1.5
x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0
mg/dL).

- No evidence of pre-existing uncontrolled hypertension as documented by 2 baseline
blood pressure (BP) readings taken at least 1 hour apart. The baseline systolic BP
readings must be ≤ 150 mm Hg, and the baseline diastolic BP readings must be ≤ 90 mm
Hg

- Patients enrolled to the prior treatment arm of the expansion cohort must have been
exposed to a TKI for metastatic disease. Exposure to TKI as part of (neo)adjuvant
treatment that completed within 1 year of study qualifies as prior exposure as well.

Exclusion Criteria:

- Prior therapy with axitinib

- Prior systemic therapy directed at advanced RCC is not allowed for patients enrolled
to the expansion cohort, treatment naïve arm. If prior (neo)adjuvant treatment given
as part of a clinical trial, this would be allowed as long as last dose was > 1 year
prior to start of treatment

- Patients enrolled to the prior treatment arm of the dose escalation cohort must not
have received anti-cancer therapy less than 14 days prior to the first dose of study
drug or palliative, focal radiation therapy less than 14 days prior to the first dose
of study drug.

- Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic
T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other
antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)

- Patients are excluded if they have active, symptomatic brain metastases or
leptomeningeal metastases. Subjects with known brain metastases are eligible if
metastases have been treated and there is no magnetic resonance imaging (MRI) evidence
of progression for four weeks (after treatment is complete and within 28 days prior to
study drug administration.

- Diagnosis of immunodeficiency

- Active, known or suspected autoimmune disease. Subjects are permitted to enroll if
they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to
autoimmune condition only requiring hormone replacement, psoriasis not requiring
systemic treatment, or conditions not expected to recur in the absence of an external
trigger

- Patients have a condition requiring systemic treatment with either corticosteroids (>
10 mg daily prednisone equivalents) or other immunosuppressive medications within 14
days of study drug administration. Inhaled or topical steroids and adrenal replacement
doses > 10 mg daily prednisone equivalents are permitted in the absence of active
autoimmune disease.

- Major surgery <4 weeks or radiation therapy <2 weeks of study entry. Prior palliative
radiotherapy to metastatic lesion(s) is permitted, provided there is at least one
measurable lesion that has not been irradiated.

- Gastrointestinal abnormalities including: Inability to take oral medication;
Requirement for intravenous alimentation; Prior surgical procedures affecting
absorption including total gastric resection; Treatment for active peptic ulcer
disease in the past 6 months; Active gastrointestinal bleeding as evidenced by
hematemesis, hematochezia or melena in the past 3 months without evidence of
resolution documented by endoscopy or colonoscopy; Malabsorption syndromes.

- Evidence of inadequate wound healing.

- Active bleeding disorder or other history of significant bleeding episodes within 30
days before study entry.

- Known prior or suspected hypersensitivity to study drugs or any component in their
formulations.

- Current use or anticipated need for treatment with drugs or foods that are known
strong CYP3A4/5 inhibitors including but not limited to atazanavir, clarithromycin,
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir,
telithromycin, troleandomycin, voriconazole, and grapefruit or grapefruit juice. The
topical use of these medications (if applicable), such as 2% ketoconazole cream, is
allowed.

- Current use or anticipated need for treatment with drugs that are known strong
CYP3A4/5 inducers, including but not limited to carbamazepine, phenobarbital,
phenytoin, rifabutin, rifampin, and St. John's wort.

- As there is potential for hepatic toxicity with nivolumab, drugs with a predisposition
to hepatotoxicity should be used with caution in patients treated with
nivolumab-containing regimen.

- Known hepatitis B virus (HBV) or hepatitis C virus (HBV) infection.

- Known history of human immunodeficiency virus (HIV) or known acquired immunodeficiency
syndrome (AIDS)

- History of any of the following cardiovascular conditions within 12 months of
screening: Myocardial infarction, Unstable angina pectoris, Cardiac angioplasty or
stenting, Coronary/peripheral artery bypass graft, Class III or IV congestive heart
failure per New York Heart Association, Cerebrovascular accident or transient ischemic
attack

- History of deep vein thrombosis or pulmonary embolism within 6 months of screening.
Patients who are currently taking anticoagulation therapy for a prior history (> 6
months from screening) of thrombosis may still be eligible.

- Pregnant or breast feeding.