Nivolumab and Stereotactic Ablative Radiation Therapy (SAbR) for Metastatic Clear Cell Renal Cell Carcinoma

A single institution, safety lead-in phase II trial with SAbR to multiple metastatic sites
concurrently administered with Nivolumab for patients with metastatic clear cell renal cell
cancer who have failed at least one anti-angiogenic therapy.

Inclusion Criteria:

- At least 18 years of age

- Willing and able to provide consent

- Pathologic diagnosis of metastatic RCC with clear cell component

- Measurable disease in at least 2 non-radiated sites. Progression or intolerance to at
least one prior systemic anti-angiogenic therapy.

- Eligible for extra-CNS SAbR to 1-6 sites of disease

- Must have received at least one prior anti-angiogenic therapy in the advanced or
metastatic setting. Prior cytokine therapy (eg, IL-2, IFN-α), vaccine therapy, or
treatment with cytotoxic therapy is also allowed but not any other drug specifically
targeting T-cell co-stimulation or checkpoint pathways.

- Previous treatment with surgery, radiation, chemotherapy, targeted agents (see above)
are allowed provided that: Chemotherapy/Major surgery was administered > 14 days
before the start Nivolumab; Minor surgery, radiation, or any targeted agents were
administered > 7 days before the start of Nivolumab

- Performance status ECOG 0, 1, 2 or 3.

- Adequate organ and marrow function as defined below (obtained within 14 days of first
dose of drug):

- leukocytes≥ 2,000/mcL

- absolute neutrophil count ≥ 1,500/mcL

- platelets ≥ 50,000/mcl

- total bilirubin ≤ 2mg/dL

- AST(SGOT)/ALT(SPGT) ≤ 3 X institutional upper limit of normal

- Women of child-bearing potential

- female of child-bearing potential is any woman (regardless of sexual orientation,
having undergone a tubal ligation, or remaining celibate by choice) who meets the
following criteria:

- must have a negative serum or urine pregnancy test within 24 hours prior to the
start of investigational product.

- Women must not be breastfeeding.

- must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry, for the duration of study
participation and contraception should be continued for a period of 30 days plus
the time required for the investigational drug to undergo five half lives.

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

- Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year. Contraception should be continued for a
period of 90 days plus the time required for the investigational drug to undergo
five half lives. This is equivalent to 31 weeks after discontinuation of
Nivolumab.

- Adequate Renal function with Cr ≤ 2.5 mg/dL.

Exclusion Criteria:

- Subjects who have had major surgery (such as nephrectomy) or chemotherapy within 2
weeks prior to first dose of drug

- Subjects who have had radiation therapy within 2 weeks prior to first dose of drug

- Uncontrolled adrenal insufficiency or active chronic liver disease

- Any history of CNS metastases that is not adequately treated with surgery or SABR >14
days prior.

- Prior treatment with any anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4
antibody, or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways.

- Any positive history for HIV/AIDS, HTLV, hepatitis B or hepatitis C virus indicating
acute or chronic infection.

- Any active known or suspected autoimmune disease. Subjects with 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 are permitted to enroll.

- Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily
prednisone equivalent) or other immunosuppressive medications within 14 days prior to
the first dose of study drug. Inhaled steroids and adrenal replacement steroid doses
up to 10 mg daily prednisone equivalent are permitted (although not encouraged) in the
absence of active autoimmune disease.

- Subjects with life expectancy < 6 months

- Subjects receiving any other investigational or standard antineoplastic agents.

- Prior malignancies active within the previous 3 years except for locally curable
cancers that have been apparently cured, such as basal or squamous cell skin cancer,
superficial bladder cancer, or carcinoma in situ of the prostate, cervix, breast?, or
etc.

- Psychiatric illness/social situations that would limit consenting and compliance with
study requirements.

- Patients with history of hypersensitivity to monoclonal antibodies

- Subjects who are pregnant or nursing due to the potential for congenital abnormalities
and the potential of this regimen to harm nursing infants