Study of Front Line Therapy With Nivolumab and Salvage Nivolumab + Ipilimumab in Patients With Advanced Renal Cell Carcinoma

Eligible patients with biopsiable (biopsied) disease will receive nivolumab 240 mg IV every 2
weeks x 6 doses then 360 mg every 3 weeks for up to 84 weeks. Tumor response will be assessed
at weeks 12, 18 and 24 and then every 12 weeks. For patients who experience RECIST 1.1
defined PD, but remain clinically stable (and asymptomatic), a confirmatory scan after 6
weeks (± 1 week) of additional therapy is suggested. Patients with persistent PD at
confirmatory scan will be evaluated for enrollment on Part B of this study. Symptomatic
patients may be evaluated for Part B immediately. Patients without confirmed PD can continue
on nivolumab therapy.

Patients who experience symptomatic or confirmed PD (or have best response of SD at 12
months) on nivolumab monotherapy will be eligible for consideration for Part B. Part B
involves the addition of ipilimumab for up to 4 doses while maintaining nivolumab therapy.
Dose of ipilimumab will be 1 mg/kg every 3 weeks together with nivolumab changed to 3 mg/kg
every 3 weeks for up to 4 doses. Nivolumab will revert to 360 mg every 3 weeks after the
completion of treatment with ipilimumab (beginning week 13-19 of Part B) for up to 48 weeks.
Patients will be followed with serial imaging assessments weeks 12, 18 and 24 and then every
12 weeks after the initiation of ipilimumab. The tumor measurements at the time of ipilimumab
institution will be the new baseline. If unequivocal symptomatic or confirmed new PD (as
defined above) develops, treatment will be discontinued.

Patients for Part B must still meet the eligibility criteria for initial study enrollment.
Patients with Grade 3 toxicity on nivolumab monotherapy, serious symptomatic disease that in
the opinion of the site investigator requires immediate use of an alternative treatment
approach or continued PR/CR will be excluded from enrolling in Part B. It is estimated that
roughly half of the patients accrued to the first-line treatment will go on to enroll in Part
B.

An additional biopsy will be performed of a metastatic lesion at time of confirmed PD in all
patients enrolling in Part B. Confirmation of tumor in the biopsy specimen must occur prior
to initiation of treatment on Part B. FFPE and frozen tissue will be stored from this sample
and used for correlative studies described below.

An additional cohort of 40 non-ccRCC patients will be enrolled and analyzed separately for
evidence of anti-tumor activity (CR, PR and SD and PFS at 1 year of nivolumab). These
patients will also be eligible for participation in Part B. We anticipate that the accrual of
these 40 patients will be able to be completed within the 1.5 years needed for accrual of the
ccRCC patients.

Part A: Nivolumab Administration. Nivolumab will be given every 2 weeks x 6 at a dose of 240
mg Intravenously (IV) and then every 3 weeks at a dose of 360 mg IV until toxicity, complete
response, disease progression, SD at 12 months or a maximum of 96 total weeks (12 weeks
induction, 84 weeks maintenance) Patients with disease progression (at any time) or SD at 12
months will be eligible to be considered for participation in Part B of the study.

Part B: Nivolumab + Ipilimumab. Patients with Grade 3 toxicity on nivolumab monotherapy,
(excluding endocrine toxicity), serious symptomatic disease that in the opinion of the site
investigator requires immediate use of an alternative treatment approach or continued PR/CR
will be excluded from enrolling in Part B. It is estimated that roughly half of the patients
accrued to the first line treatment will go on to enroll in Part B.

Ipilimumab will be given 1 mg/kg every 3 weeks together with nivolumab 240 mg every 3 weeks
for up to 4 doses. Nivolumab will revert to 3 mg/kg every 3 weeks after the completion of
combination treatment with ipilimumab .

Following the first 4 doses of the combination of nivolumab and ipilimumab, nivolumab
monotherapy will again be given every 3 weeks at a dose of 360 mg for a maximum of 48 weeks.
Patients may be dosed no less than 18 days from the previous dose of drug; and dosed up to 3
days after the scheduled date, if necessary.

Inclusion Criteria-Part A:

Subject must meet all of the following applicable inclusion criteria to participate in this
study:

- Patients must have histologically confirmed advanced RCC (any histology). Collecting
duct tumors and tumors originating from the renal pelvis or upper urinary tract are
considered of urothelial origin and are excluded from this protocol.

- Patients must have at least one measurable site of disease, per RECIST 1.1, that has
not been previously irradiated. If the patient has had previous radiation to the
marker lesion(s), there must be evidence of progression since the radiation.

- ECOG performance status 0-2

- Have signed the current approved informed consent form

Patients must have adequate organ function within 14 days prior to study entry as evidenced
by screening laboratory values that must meet the following criteria:

Hematological:

- White blood cell (WBC) ≥ 2000/µL

- Absolute Neutrophil Count (ANC) ≥ 1500/μL

- Platelets (Plt) ≥ 100 x103/μL

- Hemoglobin (Hgb) > 9.0 g/dL (with or without transfusion)

Renal:

- Serum Creatinine ≤ 1.5 x ULN; if creatinine > 1.5, subject must demonstrate CrCl as
outlined below.

- Calculated creatinine clearance ≥ 40 mL/min using Cockcroft-Gault formula

Hepatic:

- Bilirubin ≤ 1.5× upper limit of normal (ULN); Except subjects with Gilbert Syndrome,
who can have total bilirubin < 3.0 mg/dL

- Aspartate aminotransferase (AST) ≤ 3 × ULN

- Alanine aminotransferase (ALT) ≤ 3 × ULN

- Archival tissue is mandatory (a tumor biopsy- core or excisional) of a metastatic
lesion obtained within 1 year prior to study registration (within 4 weeks preferred).
Tumor tissue from nephrectomy and site of metastasis will be required. If archival
tissue of a metastatic lesion obtained within the preceding year is not available,
patients must have at least one site of disease (not including bone metastases)
accessible for core needle or excisional biopsy. If archival tissue of a metastatic
lesion is not available and biopsy of a new lesion is not feasible, the subject is not
eligible for the study.

- Patients should not have received prior systemic therapy for metastatic RCC. Prior
radiotherapy must have been completed at least 2 weeks prior to the administration of
study drug. Patients must be 2 weeks from prior major surgery and 1 week from
pre-treatment biopsy. Prior systemic adjuvant therapy (excluding with PD1 or CTLA4
pathway blockers) is allowed if treatment completed > 12 months previously.

- Women of childbearing potential (WOCBP) must use appropriate method(s) of
contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks

- Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG) during screening for
registration purposes. This pregnancy test should be repeated within 24 hours prior to
the start of nivolumab.

- Women must not be breastfeeding

- Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year Men receiving nivolumab and who are sexually
active with WOCBP will be instructed to adhere to contraception for a period of 31
weeks after the last dose of investigational product Women who are not of childbearing
potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men
do not require contraception.

- Be willing and able to comply with this protocol.

Exclusion Criteria:

- Patients are excluded if they have active brain metastases or leptomeningeal
metastases. Subjects with brain metastases are eligible if metastases have been
treated and there is no magnetic resonance imaging (MRI) evidence of progression for 2
weeks of more after treatment is complete and within 28 days prior to the first dose
of nivolumab administration. There must also be no requirement for immunosuppressive
doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2
weeks prior to study drug administration.

- Patients with controlled brain metastases are allowed on protocol if they had solitary
brain metastases that was surgically resected without recurrence or treated with SRS
without progression x 4 weeks.

- Patients should be excluded if they have an 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 should be excluded if they 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.

- As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab
combinations, drugs with a predisposition to hepatoxicity should be used with caution
in patients treated with nivolumab-containing regimen

- Active infection requiring systemic therapy

- Has any other medical or personal condition that, in the opinion of the site
investigator, may potentially compromise the safety or compliance of the patient, or
may preclude the patient's successful completion of the clinical trial

- Patients should be excluded if they are positive test for hepatitis B virus surface
antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating
acute or chronic infection

- Patients should be excluded if they have known history of testing positive for human
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)

- Allergies and Adverse Drug Reaction

- History of allergy to study drug components

- History of severe hypersensitivity reaction to any monoclonal antibody

- Known additional malignancies within the past 3 years (excluding basal of squamous
cell skin cancers, CIS or localized prostate cancer that has been treated or is being
observed)

Inclusion/Exclusion Criteria- Part B

- Must meet eligibility criteria for initiation of Part A with the exception of being
allowed to have prior nivolumab in Part A of this protocol

- Must have evidence of either RECIST 1.1 defined Disease Progression or Stable Disease
1 year after initiating nivolumab therapy

- Must undergo repeat tumor biopsy for acquisition of resistant tumor tissue

- Must not have had a Grade ≥ 3 irAE on nivolumab monotherapy

- Must not have untreated brain metastases

- Must not have had major surgery or radiation therapy within 14 days of starting study
treatment

- Must not have active autoimmune disease

- Must not have a concurrent medical condition requiring use of systemic corticosteroids
with prednisone >10 mg per day

- Must not have had prior systemic therapy for Stage IV RCC (except for nivolumab as
part of part A of this protocol)

- Prior solid organ or stem cell transplant