Tremelimumab With or Without Cryoablation in Treating Patients With Metastatic Kidney Cancer

PRIMARY OBJECTIVES:

I. To evaluate safety of tremelimumab alone and in combination with cryoablation in patients
with metastatic renal cell carcinoma (RCC).

SECONDARY OBJECTIVES:

I. To explore the longitudinal values for immunological variables (including cluster of
differentiation [CD]4+ ICOS+ T cells; effector to regulatory T cell ratio; absolute
lymphocyte count) following treatment with tremelimumab in patients with metastatic RCC, and
evaluate difference between combination cryoablation and tremelimumab in comparison to
tremelimumab alone.

II. To determine the objective response rate and progression-free survival of patients
treated with tremelimumab with or without cryoablation.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive tremelimumab intravenously (IV) over 60 minutes at weeks 1 and 5.
Within 4-6 weeks later, patients undergo surgery or biopsy. After surgery or biopsy, patients
receive tremelimumab IV every 4 weeks (Q4W) for 3 doses, and then every 12 weeks (Q12W) in
the absence of disease progression or unacceptable toxicity.

ARM B: Patients undergo cryoablation and receive tremelimumab IV over 60 minutes at weeks 1
(2-6 days after cryoablation) and 5. Within 4-6 weeks later, patients undergo surgery or
biopsy. After surgery or biopsy, patients receive tremelimumab IV Q4W for 3 doses, and then
Q12W in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30, 60, and 90 days, and
then every 6 months.

Inclusion Criteria:

- Metastatic renal cell carcinoma (clear cell or non clear cell)

- One metastatic site amenable to cryoablation

- Patients with a single metastatic site may be enrolled if that site is amenable
to ablation; however these patients will not be counted in secondary measures of
response unless there is new disease detected during follow up

- Eligible for cytoreductive nephrectomy, metastasectomy, or repeated biopsy;
biopsy site cannot be lung, mediastinal lymph node, or bone (unless soft tissue
component)

- Patients with any number of prior therapies with anti-angiogenic agents or
immunotherapy with the exception of any previous anti-CTLA-4 directed agents are
allowed; a 2 week washout period is required for all agents, except for bevacizumab
where a 4 week washout is required

- Performance status with Eastern Cooperative Oncology Group (ECOG) score =< 2; patients
with performance status of 3 may be considered as long as the decline has been of
short duration (< 1 month), and is due to their malignancy and not a comorbid
condition (example: pain limiting activity)

- Patient's with an International Metastatic Renal Cell Carcinoma Database Consortium
(IMDC or Heng) score of 3 or less will be included; score greater than 4 will be
excluded; 1 point each: requirement of systemic treatment for metastatic disease less
than 1 year of original diagnosis of renal cell carcinoma, a serum calcium greater
than 10, anemia, neutrophilia, thrombocytosis, ECOG performance status >= 2

- No history of autoimmune disorders

- White blood cell (WBC) >= 2000/uL

- Absolute neutrophil count (ANC) >= 1000/uL

- Platelets >= 75 x 10^3/uL

- Hemoglobin >= 9 g/dL

- Creatinine =< 3 x upper limit of normal (ULN)

- Alanine aminotransferase (ALT) =< 3.0 x ULN for patients without liver metastases; for
patients with liver metastasis ALT =< 5 x ULN is allowed

- Bilirubin =< 1.5 x ULN (except for patients with Gilbert's syndrome, who must have a
total bilirubin =< 3 mg/dL)

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

- Females of childbearing potential who are sexually active with a non-sterilized male
partner and non-sterilized males must use a highly effective method of contraception
for 28 days prior to the first dose of investigational product, and must agree to
continue using such precautions for 180 days after the final dose of investigational
product; cessation of contraception after this point should be discussed with a
responsible physician; periodic abstinence, the rhythm method, and the withdrawal
method are not acceptable methods of contraception; they must also refrain from egg
cell donation for 180 days after the final dose of investigational product; females of
childbearing potential are defined as those who are not surgically sterile (ie,
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or
postmenopausal (defined as 12 months with no menses without an alternative medical
cause); a highly effective method of contraception is defined as one that results in a
low failure rate (ie, less than 1% per year) when used consistently and correctly; the
acceptable methods of contraception are: barrier method (e.g. male condom with
spermicide, copper T intrauterine device, or levonorgestrel-releasing intrauterine
system - Mirena) or hormonal methods (e.g. implants, hormone shot or injection,
combined pill, minipill, or patch)

Exclusion Criteria:

- Unresolved toxicities from prior anticancer therapy, defined as having not resolved to
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
version (v)4.03 grade 0 or 1 with the exception of alopecia and laboratory values
listed per the inclusion criteria

- Known or suspected autoimmune disease; patients with a history of inflammatory bowel
disease (including Crohn's disease and ulcerative colitis) and autoimmune disorders
such as rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic
lupus erythematosus or autoimmune vasculitis [e.g., Wegener's granulomatosis] are
excluded from this study; patients with a history of Hashimoto's thyroiditis only
requiring hormone replacement, type I diabetes, or psoriasis not requiring systemic
treatment, or conditions not expected to recur in the absence of an external trigger
are allowed to participate

- Any condition requiring systemic treatment with corticosteroids (> 10 mg daily
prednisone equivalents) or other immunosuppressive medications within 14 days prior to
first dose of study drug; inhaled steroids and adrenal replacement steroids doses > 10
mg daily prednisone equivalents are permitted in the absence of active autoimmune
disease

- Autoimmune disease: patients with a history of inflammatory bowel disease (including
Crohn's disease and ulcerative colitis) and autoimmune disorders such as rheumatoid
arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus
or autoimmune vasculitis (e.g., Wegener's granulomatosis) are excluded from this study

- Any underlying medical or psychiatric condition, which in the opinion of the
investigator, will make the administration of study drug hazardous or obscure the
interpretation of adverse events (AEs), such as a condition associated with frequent
diarrhea

- Patients with untreated brain metastases

- Major surgery within 4 weeks of enrollment

- History of other malignancies, other than non-melanoma skin cancer, Ta or T1 (low
grade) bladder carcinomas, or other low grade cancer of very low clinical impact,
unless in complete remission and off therapy for that disease for at least 2 years

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

- Known human immunodeficiency virus (HIV), hepatitis B, or hepatitis C

- Untreated symptomatic spinal cord compressions

- Any non-oncology live or attenuated vaccine therapy used for prevention of infectious
diseases within 30 days prior to the first dose of tremelimumab; if patients is
enrolled, patient should not receive live vaccine during the study and 180 days after
the last dose of tremelimumab

- Concomitant therapy with any of the following: interleukin 2 (IL-2), interferon or
other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive
agents; other investigation therapies; or chronic use of systemic corticosteroids
(used in the management of cancer or non-cancer-related illnesses)

- Previous participation in tremelimumab or ipilimumab clinical trial or prior treatment
with a CD137 agonist or CTLA-4 inhibitor or agonist

- Female subjects who are pregnant, breast-feeding or male or female patients of
reproductive potential who are not employing an effective method of birth control from
screening to 90 days after the last dose of tremelimumab monotherapy