Nivolumab in Treating Patients With High-Risk Kidney Cancer Before Surgery

PRIMARY OBJECTIVES:

I. To study the safety and feasibility of preoperative nivolumab administration in subjects
with resectable, high-risk, non-metastatic and metastatic renal cell carcinoma undergoing
planned cytoreductive nephrectomy or metastasectomy.

SECONDARY OBJECTIVES:

I. To assess overall response rate in patients receiving preoperative nivolumab.

II. To assess recurrence free survival at 2 years in patients receiving preoperative
nivolumab in patients with high-risk, non-metastatic disease.

EXPLORATORY OBJECTIVES:

I. To evaluate the association between baseline tumor mutational burden and both immune
infiltration and radiographic tumor response to nivolumab.

II. To explore predicted and expressed tumor neoantigens and their correlation with
radiographic tumor response to nivolumab.

III. To explore the association between the predicted immune signature (via ribonucleic acid
sequencing [RNAseq]) in the tumor microenvironment with radiographic tumor response to
nivolumab.

IV. To determine whether changes in the tumor microenvironment before, during, and after
therapy are associated with response.

V. To assess the potential association between PD-L1 expression (by immunohistochemistry
[IHC]) and radiographic tumor response to nivolumab.

OUTLINE:

Patients receive nivolumab intravenously (IV) over 60 minutes on days -56, -42, -28, and -14
in the absence of disease progression or unacceptable toxicity. Patients then undergo
nephrectomy or metastasectomy on day 0.

After completion of study treatment, patients are followed up at 14-28 days, at 90 days, and
then at 24-28 months.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed clear cell renal cell
carcinoma (RCC)

- For non-metastatic patients, the preoperative Memorial Sloan-Kettering (MSK) nomogram
estimates the patient's likelihood of freedom from metastatic recurrence within the
first 12 years following radical or partial nephrectomy to be =< 80%

- Measurable disease, defined as at least one lesion that can be accurately measured in
at least one dimension (longest diameter to be recorded for non-nodal lesions and
short axis for nodal lesions) as >= 20 mm (>= 2 cm) with conventional techniques or as
>= 10 mm (>= 1 cm) with spiral computed tomography (CT) scan, magnetic resonance
imaging (MRI), or calipers by clinical exam

- Non-metastatic disease will be defined by no evidence of metastases other than
regional lymphadenopathy as assessed by imaging of the chest, abdomen and pelvis with
CT of the chest and CT or MRI of the abdomen; regional lymph nodes, per 7th edition
American Joint Committee on Cancer (AJCC) staging manual (2010) for kidney cancer,
include the following positions: renal hilar, precaval, paracaval, retrocaval,
interaortocaval, paraaortic, preaortic, and retroaortic

- Scheduled to undergo nephrectomy or metastasectomy as part of treatment plan, per
assessment through an MSK urologic surgeon or medical oncologist listed as
investigator on this trial

- Availability of a frozen biopsy core prior to cycle 1, day 1

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Karnofsky >=
80%)

- Leukocytes >= 2,500/mcL

- Absolute neutrophil count >= 1,500/mcL (without granulocyte colony-stimulating factor
support within 2 weeks prior to cycle 1, day 1)

- Platelets >= 100,000/mcL (without transfusion within 2 weeks prior to cycle 1, day 1)

- Hemoglobin >= 9.0 g/dL (patients may be transfused to meet this criterion)

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (except patients
with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x ULN

- Creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the
Cockcroft-Gault formula)

- The effects of nivolumab on the developing human fetus are unknown; for this reason,
women of child-bearing potential (WOCBP) and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation; WOCBP should use an adequate method
to avoid pregnancy for 23 weeks after the last dose of investigational drug; women of
childbearing potential must have a negative serum or urine pregnancy test (minimum
sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within
14 days 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 (i.e.,
who are postmenopausal or surgically sterile as well as azoospermic men) do not
require contraception

- Women of childbearing potential (WOCBP) is defined as any female who has experienced
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral
oophorectomy) or who is not postmenopausal; menopause is defined clinically as 12
months of amenorrhea in a woman over 45 in the absence of other biological or
physiological causes; in addition, women under the age of 55 must have a documented
serum follicle stimulating hormone (FSH) level greater than 40 mIU/mL

- WOCBP receiving nivolumab will be instructed to adhere to contraception for a period
of 23 weeks after the last dose of investigational product; 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; these
durations have been calculated using the upper limit of the half-life for nivolumab
(25 days) and are based on the protocol requirement that WOCBP use contraception for 5
half-lives plus 30 days and men who are sexually active with WOCBP use contraception
for 5 half-lives plus 90 days

- Should a woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she (or the participating partner) should inform the
treating physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Prior receipt of systemic checkpoint inhibitor therapy for renal cell carcinoma

- Inability to safely delay surgery by 8 weeks as per surgeon's discretion

- Patients who are receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to nivolumab

- History of severe hypersensitivity reaction to any monoclonal antibody

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study because nivolumab has a potential for
teratogenic or abortifacient effects; because there is an unknown but potential risk
for adverse events in nursing infants secondary to treatment of the mother with
nivolumab, breastfeeding should be discontinued if the mother is treated with
nivolumab

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

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

- Patients with active autoimmune disease or history of autoimmune disease that might
recur, which may affect vital organ function or require immune suppressive treatment
including systemic corticosteroids, should be excluded; these include but are not
limited to patients with a history of immune related neurologic disease, multiple
sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia
gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE),
connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's,
ulcerative colitis, hepatitis; and patients with a history of toxic epidermal
necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be
excluded; patients with rheumatoid arthritis and other arthropathies, Sjogren's
syndrome, psoriasis controlled with topical medication, and patients with positive
serology, such as antinuclear antibodies (ANA) or anti-thyroid antibodies, should be
evaluated for the presence of target organ involvement and potential need for systemic
treatment but should otherwise be eligible

- Patients 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 (precipitating event)

- Patients should be excluded if they have a condition requiring systemic treatment with
either corticosteroids or other immunosuppressive medications within 14 days of study
drug administration; patients are permitted to use topical, ocular, intra-articular,
intranasal, and inhalational corticosteroids (with minimal systemic absorption); a
brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for
treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction
caused by contact allergen) is permitted

- Diagnosis of any second malignancy within the last 5 years prior to cycle 1, day 1,
with the exception of those with a negligible risk of metastasis or death, per
investigator's discretion (such as adequately treated carcinoma in situ of the cervix,
basal or squamous cell skin cancer, localized prostate cancer treated surgically with
curative intent, ductal carcinoma in situ treated surgically with curative intent)

- Use of live vaccines against infectious disease (e.g. varicella) within 28 days of
initiation of study therapy; killed vaccinations (e.g. influenza) are allowed at any
appropriate time before and during the study

- Life expectancy < 3 months, per consenting investigator's opinion