Phase Ib/II Trial of Interleukin-2 and PD-1 Checkpoint Inhibitor, Nivolumab In Metastatic Clear Cell Renal Cell Cancer

Inclusion Criteria:

- Subjects must have a histologic diagnosis of clear cell renal cell carcinoma (pure or
mixed) with radiologic or histologic or cytologic evidence of metastatic disease.

- Subjects may have received up to 2 prior lines of systemic therapy (excluding any
neoadjuvant/adjuvant therapy) including anti-VEGF or VEGFR inhibitor (e.g. sorafenib,
pazopanib, sunitinib, bevacizumab, axitinib) or mTOR inhibitor (e.g. everolimus or
temsirolimus) for metastatic disease.

- Age ≥ 18 years at the time of consent.

- ECOG (Eastern Cooperative Oncology Group) performance status (an attempt to quantify
cancer patients' general well-being and activities of daily life. The score ranges
from 0 to 5 where 0 is asymptomatic and 5 is death.) of 0 or 1

- Adequate organ and marrow function

- Women of childbearing potential must have a negative serum or urine pregnancy test
within 28 days prior to prior to registration. Women of non-childbearing potential are
defined as those who have no uterus, ligation of the fallopian tubes, or permanent
cessation of ovarian function due to ovarian failure or surgical removal of the
ovaries. All others are considered women of child bearing potential.

- Females and males of childbearing potential must be willing to use an effective method
of contraception (hormonal or barrier method of birth control; abstinence) from the
time consent is signed until 6 months after treatment discontinuation.

- Subjects must have measurable disease on physical exam or imaging

- An archived tissue block with the subject's renal cell carcinoma must be identified
prior to registration.

- Subjects must be considered appropriate candidates for HD IL-2 by one of the treating
investigators listed on the protocol. HD IL-2 candidacy evaluation is per
institutional guidelines at each site and should include a dobutamine stress
echocardiogram or equivalent. Subjects with a positive stress test for cardiac
ischemia would be excluded from this trial.

- No clinically significant infections or any other medical condition(s) that render the
subject ineligible for high dose IL-2 therapy as judged by the treating investigator.

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

Exclusion Criteria:

- Prior interferon or interleukin-2 therapy is NOT allowed.

- Prior anti-PD-1/PD-L1 targeted therapy is NOT allowed. Prior CTLA-4 therapy or
CD40/CD40L targeted therapy is allowed.

- Prior systemic treatment must be completed at least 14 calendar days prior to
registration and the subject must have recovered from the toxicities of treatment to
grade 1 or better.

- Prior radiation therapy is allowed if completed at least 14 calendar days prior to
registration.

- Treatment with any investigational agent or on an interventional clinical trial within
30 days prior to registration.

- No prior or concurrent malignancy is allowed except for: adequately treated basal cell
or squamous cell skin cancer, in situ cervical cancer, localized or locally advanced
prostate cancer definitively treated without recurrence or with biochemical recurrence
only, or any other cancer fully treated or from which the subject has been
disease-free for at least 2 years.

- Current untreated brain metastasi(e)s. If treated history of CNS (central nervous
system) metastases, should have completed radiation or surgery at least 12 weeks prior
and off systemic corticosteroids.

- Autoimmune diseases such as rheumatoid arthritis are NOT allowed. Vitiligo, mild
psoriasis (topical therapy only) or hypothyroidism are allowed.

- Medical need for systemic corticosteroids >10mg prednisone daily or equivalent
alternative steroid (except physiologic dose for adrenal replacement therapy) or other
immunosuppressive agents (such as cyclosporine or methotrexate) Topical and inhaled
corticosteroids are allowed if medically needed.

- History of allergic reaction to interleukin-2 or nivolumab

- Prior history of psychiatric disorder or seizure disorders which could be exacerbated
by Interleukin-2 as judged by the treating investigator. 3.2.12 Evidence of
significant cardiovascular disease including history of recent (< 6 months prior)
myocardial infarction, congestive heart failure, primary cardiac arrhythmias (not due
to electrolyte disorder or drug toxicity, for example) beyond occasional PVC's
(premature ventricular contractions), angina, positive low-level stress test, or
cerebrovascular accident. All patients should have baseline pulmonary function tests.
Adequate pulmonary function should be documented (FEV1 >2 liters or ≥75% of predicted
for height and age) prior to initiating therapy.

- Any history of HIV or hepatitis B infection

- Any other medical or surgical condition or disease that, in the judgment of the
treating physician, renders subject ineligible for High Dose Interleukin-2 therapy.

- Any history of organ allografts