Interleukin-2 and Pembrolizumab for Metastatic Kidney Cancer

The treatment is organized into blocks of 9 weeks, with pembrolizumab treatment planned for
weeks 1, 4 and 7. On the second and third blocks, interleukin-2 is added, for 5 doses at a
time, one dose every 8 hours, on a weekly schedule on the two weeks after the week 1 and the
week 4 pembrolizumab doses.

There is no dose escalation portion: The dose and schedule of IL-2 is fixed, 600,000
IU/kg/dose, with a cap of 66 mIU/dose. Doses may be omitted for safety. The dose of
pembrolizumab is fixed, flat dose 200 mg/dose.

Inclusion Criteria:

- Diagnosis/Condition for Entry into the Trial: Metastatic kidney cancer. Clear cell
histology component from primary or metastatic lesion.

- Willing and able to provide written informed consent for the trial.

- Age over 18 on day of signing informed consent.

- Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
1.1.

- Willing to provide tissue from a newly obtained or archival tissue, if available.

- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
Performance Scale.

- Demonstrate adequate organ function, as outlined in Table 1 of study protocol
document.

- Females of childbearing potential must have a negative urine or serum pregnancy within
72 hours prior to receiving the first dose of study medication. If the urine test is
positive or cannot be confirmed as negative, a serum pregnancy test will be required.

- Females of childbearing potential must agree to use 2 methods of birth control or be
surgically sterile, or abstain from heterosexual activity for the course of the study
through 120 days after the last dose of study medication.

- Males must agree to use an adequate method of contraception starting with the first
dose of study therapy through 120 days after the last dose of study therapy.

- Cardiac testing with either exercise stress test or thallium stress test, within 3
months of start of the first treatment day. Atrial fibrillation that is rate
controlled is allowed. Note - the first treatment day is about 9 weeks before the
first IL-2 treatment day. If a cardiologist's evaluation determines that this is
superfluous based on other assessments, then this may be omitted.

- Pulmonary function test is required, within 3 months of start.

Exclusion Criteria:

- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment.

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment.

- Has a known history of active Bacillus Tuberculosis (TB).

- Has hypersensitivity to pembrolizumab or any of its excipients.

- The number of prior therapies is restricted as follows: (a) Zero or one prior
therapies during the preceding one year. This serves to limit the treatment cohort to
patients with either only slowly progressive disease, or up to one prior therapy. (b)
No prior PD-1 or PD-L1 antibody therapies are allowed. (c) Prior IL-2 is allowed, if
it finished more than 1 year prior. (d) The following are not counted as medical
therapies: nephrectomy, radiation therapy, other energy-ablative techniques, or
metastasectomy.

- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
due to agents administered more than 4 weeks earlier.

- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
baseline) from adverse events due to a previously administered agent. - Note: Subjects
with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the
study. - Note: If subject received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy.

- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.

- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Potential participants with previously treated brain metastases may
participate provided they are stable (without evidence of progression by imaging for
at least four weeks prior to the first dose of trial treatment and any neurologic
symptoms have returned to baseline), have no evidence of new or enlarging brain
metastases, and are not using steroids for at least 7 days prior to trial treatment.
This exception does not include carcinomatous meningitis which is excluded regardless
of clinical stability.

- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment that would be exclusionary.

- Has known history of, or any evidence of active, non-infectious pneumonitis.

- Has an active infection requiring systemic therapy.

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with participation for the
full duration of the trial, or is not in the best interest of the patient to
participate, in the opinion of the treating investigator.

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.

- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., hepatitis C
virus (HCV) RNA [qualitative] is detected).

- Has received a live vaccine within 30 days of planned start of study therapy. Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.

- Myocardial infarction, stroke, coronary artery bypass surgery, coronary stent, or
unstable angina within one year.