Aldesleukin and Pembrolizumab in Treating Patients With Advanced or Metastatic Kidney Cancer

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of aldesleukin (IL-2) combined with pembrolizumab
(MK-3475) in patients with metastatic clear cell renal cell carcinoma (RCC).

SECONDARY OBJECTIVES:

I. To assess preliminary antitumor activity of pembrolizumab in combination with IL-2.

EXPLORATORY OBJECTIVES:

I. To investigate the association of PD-L1 protein expression by pretreatment tumor with
response to treatment.

II. To investigate the association of regulatory T cell (Treg) frequency and Treg to effector
T cell (Teff) ratios in peripheral blood and tumor tissue with response to therapy.

III. To investigate the association of de novo serological and cellular responses against the
ubiquitous RCC tumor antigen 5T4 with response to therapy.

IV. To investigate the association of tumor infiltrating lymphocyte (TIL) repertoire
clonality with response to therapy and to assess the detection of dominant TIL clones within
peripheral blood over time in responding patients.

V. To investigate the association of whole genome copy number alterations measured on
pretreatment archived, formalin fixed, paraffin embedded (FFPE) tumor with response to
therapy.

OUTLINE: This is a dose-escalation study of aldesleukin.

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Patients also
receive aldesleukin subcutaneously (SC) weekly on days 1-5 of courses 1 and 2 or aldesleukin
IV on days 2-6 of courses 1 and 2. Treatment repeats every 3 weeks for up to 4 courses in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for every 3 months for up to 1
year.

Inclusion Criteria:

- Be willing and able to provide written informed consent for the trial

- Have histologic confirmation of RCC with a clear cell component

- Have advanced (not amenable to potentially curative surgery) or metastatic RCC

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

- Available tissue from an archival tissue sample or newly obtained core or excisional
biopsy of a tumor lesion

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

- Absolute neutrophil count (ANC) >= 1,500 /mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L

- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated
creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
creatinine or CrCl) >= 40 mL/min for subject with creatinine levels > 1.5 X
institutional ULN; creatinine clearance should be calculated by Cockcroft-Gault

- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X
ULN OR =< 5 X ULN for subjects with liver metastases

- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants

- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
of anticoagulants

- Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) >= 65% of
predicted (patients >= 40 years old)

- Left ventricular ejection fraction (LVEF) >= 50% measured by multigated acquisition
(MUGA) scan, echo, or stress test study with myocardial perfusion imaging

- Normal/negative cardiac stress testing with myocardial perfusion imaging OR cardiac
catheterization with non-significant angiogram findings reviewed by a cardiology
consultant (dose level 3 and >= 40 years old)

- Female subject of childbearing potential should have a negative urine or serum
pregnancy test 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

- Female subjects of childbearing potential should be willing 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; subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for > 1 year

- Male subjects should 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

Exclusion Criteria:

- (Dose levels 1 and 2) - may have received one or more systemic treatments or regimens
for metastatic RCC; (dose level 3) - cannot have received prior systemic treatment for
RCC

- Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways)

- Has received prior therapy with IL-2 or other investigational systemic cytokine
therapy signaling through a common gamma-chain cytokine receptor including IL-7, IL-15
or IL-21

- Is currently participating in or has participated in a study of an investigational
agent or using an investigational device within 4 weeks of the first dose of treatment

- Has had a prior monoclonal antibody 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: 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 locally curable cancers such as basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ
of the cervix or breast that has undergone potentially curative therapy

- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis

- (Dose level 1) subjects 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

- (Dose Level 2 and 3) subjects may not have any history of or current CNS
metastases; baseline imaging of the brain is required within 28 days prior to the
start of study treatments

- 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 an active autoimmune disease requiring systemic treatment within the past 3 months
or a documented history of clinically severe autoimmune disease, or a syndrome that
requires systemic steroids or immunosuppressive agents; subjects with vitiligo or
resolved childhood asthma/atopy would be an exception to this rule; subjects that
require intermittent use of bronchodilators or local steroid injections would not be
excluded from the study; subjects with hypothyroidism stable on hormone replacement or
Sjorgen's syndrome will not be excluded from the study

- Has history of (non-infectious) pneumonitis that required steroids or active,
non-infectious pneumonitis

- Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or
prolongation of the corrected QT interval defined as > 450 msec for males and > 470
msec for female

- History of any of the following cardiovascular conditions within 6 months of
enrollment: cardiac angioplasty or stenting, myocardial infarction, unstable angina,
coronary artery bypass graft surgery, class III or IV congestive heart failure as
defined by the New York Heart Association, symptomatic peripheral vascular disease,
cerebrovascular accident, or transient ischemic attack

- 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 the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject 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 a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

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

- Has received a live vaccine within 30 days prior to the first dose of trial treatment;
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