Yttrium-90 Radioembolization + Nivolumab for Liver + Extra-hepatic Metastases From Colorectal Cancer

Primary Objective

Phase Ib: To determine the safety and tolerability of Y-90 radioembolization therapy when
given in conjunction with neoadjuvant/adjuvant nivolumab as assessed by CTCAE version 4, in
patients with metastatic colorectal cancer who undergo Y-90 radioembolization to hepatic
metastases and have additional disease located outside of the radioembolization field.

Phase II: To determine the objective response rate (RR) as assessed by RECIST criteria of
metastases located outside of the Y-90 radioembolization treatment field in patients with
metastatic colorectal cancer who undergo Y-90 radioembolization to hepatic metastases and
receive neoadjuvant/adjuvant nivolumab.

Secondary Objectives

Phase Ib:

To assess the response rate (RR) of patients with metastatic colorectal cancer who undergo
standard Y-90 radioembolization therapy to hepatic metastases as well as neoadjuvant/adjuvant
nivolumab as assessed by measurement of foci located outside of the Y-90 radioembolization
field.

Phase II:

To assess the progression free survival (PFS) of patients with metastatic colorectal cancer
who undergo standard Y-90 radioembolization therapy to hepatic metastases as well as
neoadjuvant/adjuvant nivolumab as assessed by measurement of metastatic foci located outside
of the Y-90 radioembolization field.

To assess the 1-year and 2-year overall survival (OS) rate of patients with metastatic
colorectal cancer who undergo standard Y-90 radioembolization therapy to hepatic metastases
as well as neoadjuvant/adjuvant nivolumab.

Correlative Objectives

To characterize the baseline expression and localization of immune markers including
Programmed cell death protein 1 (PD-1), Programmed cell death protein ligand 1 (PD-L1),
Programmed cell death protein ligand 2 (PD-L2), T-cell immunoglobulin and mucin-domain
containing-3 (TIM-3), Lymphocyte activation gene 3 (LAG-3), Tumor necrosis factor receptor
superfamily, member 4 (OX40) and Cluster of Differentiation 137 (CD137) within the tumor
microenvironment and correlate this with treatment response.

To examine the change in density of Cluster of Differentiation (CD8)+/Kiel-67 (Ki-67) high
tumor infiltrating lymphocytes and expression levels of PD-L1 in the tumor parenchyma prior
to and following treatment with Y-90 and nivolumab as assessed in a lesion outside of the
radioembolization field. Changes in biomarkers will be correlated with treatment response.

To assess baseline and changes in the immune signature of Y-90 naïve colorectal cancer in
patients with liver metastases who receive Y-90 radioembolization and nivolumab therapy.
Human transcriptome gene expression arrays will be performed and expression data will be used
to identify immune cell subsets using CIBERSORT and immune signatures will be assessed using
ImmuneSigDB.

To assess baseline and changes in non-targeted tumor antigens using Proto Array Human Protein
MicroArray Profiling and Immunoglobulin G (IgG) quantification in patients with liver
metastases who receive Y-90 radioembolization and nivolumab therapy. Changes in profile will
be correlated with treatment response.

Study Design

This is a single arm phase Ib/II trial assessing the safety and toxicity (phase Ib) followed
by the antitumor activity (response rate) (phase II) of nivolumab when administered in
combination with Y-90 radioembolization therapy.

Study design

Eligible patients will undergo Y-90 radioembolization to one side of the liver according to
standard practice as directed by an interventional radiologist. Yttrium-90 will be given as
biocompatible resin-based microspheres and will be introduced to the tumor(s) on one side of
the liver through a catheter placed in the right or left hepatic artery (depending on the
lobe treated). The dose of radiation will be determined by a radiologist and will be based on
body surface area and tumor burden. During the phase Ib portion of the study, nivolumab will
be administered per the scheduling algorithm at a flat dose of 240 mg intravenously over 30
+/- 5 minutes. Depending on the schedule being assessed, this may include a neoadjuvant dose
to be given prior to Y-90, and will contain an adjuvant dose following Y-90 therapy. During
the phase II portion of the study, nivolumab will be administered as determined during the
phase Ib portion of the study. Nivolumab will continue to be administered on an every 2 week
basis for a total of 48 weeks or until disease progression, unacceptable toxicity or
discontinuation due to patient/physician preference. Patients will be evaluated with a
history and physical exam as well as laboratory parameters once every 2 weeks throughout the
duration of the study. Patients will undergo CT scans of the chest and pelvis as well as MRI
of the liver to assess disease status 2 months following the Y-90 radioembolization
procedure, then every 3 months for a total of 2 years. Upon completing treatment, patients
will be followed monthly for another 100 days for toxicity monitoring. Archived tissue
specimens will be obtained at baseline and a post-treatment biopsy of a metastatic lesion
located outside of the Y-90 radioembolization field will be obtained 60 +/- 5 days following
treatment with Y-90 radioembolization for assessment of intratumoral immunogenicity.
Carcinoembryonic antigen (CEA) levels will be assessed at baseline, then once monthly for 6
months, then every 3 months for a total of 2 years. Patients will have a pre-treatment serum
sample collected as well as post-treatment samples collected approximately 6 weeks, 12 weeks
and 20 weeks after treatment with Y-90 radioembolization for banking, to be used in the
future assessment of putative biomarkers.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed metastatic colorectal
cancer.

- Patients must have liver metastases and be appropriate for treatment with Y-90
radioembolization therapy as determined by the treating medical oncologist and
interventional radiologist. Prior Y-90 therapy is not permitted.

- Patients must have measurable disease that is located outside of the Y-90
radioembolization field.

- Patients must have a metastatic focus amenable to biopsy that is located outside of
the Y-90 radioembolization field. It is permissible to use the same lesion for biopsy
as for assessment to tumor response.

- Patients must have received at least one line of prior chemotherapy and must have had
resolution of all side effects to at least at Grade 1 prior to trial entry.

- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0-1.

- Patients must have normal organ and marrow function as defined below:

- Hemoglobin ≥ 9.0 g/dl

- Leukocytes ≥ 2,000/mcL

- Absolute neutrophil count ≥ 1,500/mcL

- Platelet count ≥ 100,000/mcL

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (except in patients with
Gilbert Syndrome, who can have a total bilirubin < 3.0 mg/dL)

- Aspartate aminotransferase (AST) (SGOT) ≤ 3 X institutional upper limit of normal

- Alanine aminotransferase (ALT) (SGPT) ≤ 3 X institutional upper limit of normal

- Serum creatinine ≤ 1.5 X ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using
the Cockcroft-Gault formula below):

Female CrCl = (140 - age in years) x weight in kg x 1.00/ 72 x serum creatinine in mg/dL

Male CrCl = (140 - age in years) x weight in kg x 1.00/ 72 x serum creatinine in mg/dL

-Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception.
WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time
required for nivolumab to undergo five half-lives) after the last dose of investigational
drug. Women of childbearing potential" is defined as any female who has experienced
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral
oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of
amenorrhea in a woman over 45 in the absence of other biological or physiological causes.
In addition, women under the age of 62 must have a documented serum follicle stimulating
hormone (FSH) level less than 40 mili-international units/milliliter (mIU/mL).

Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on
the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise on the use of highly effective methods of contraception, with
have a failure rate of < 1% when used consistently and correctly.

- Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the
start of nivolumab.

- Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year. Men receiving nivolumab and who are sexually
active with WOCBP will be instructed to adhere to contraception for a period of 31
weeks after the last dose of investigational product. Women who are not of
childbearing potential (i.e., who are postmenopausal or surgically sterile as well as
azoospermic men do not require contraception).

- Patients must have the ability to understand and the willingness to sign a written
informed consent document

Exclusion Criteria:

- Patients with ongoing toxicities > grade 1 according to NCI CTCAE Version 4.0
(excluding alopecia and neuropathy) due to prior anti-cancer therapy.

- Patients receiving any other investigational agent or active chemotherapy.

- Patients who have previously been treated an anti-PD-1, anti-PD-L1, anti-PD-L2,
anti-Cytotoxic T-lymphocyte associated protein (CTLA)-4 antibody, or any other
antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint
pathways.

- Patients with a known autoimmune disease. Patients are permitted to enroll if they
have 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.

- Patients having a condition requiring systemic treatment with either corticosteroids
(> 10 mg/day prednisone equivalents) or other immunosuppressive medications within 14
days of study drug administration. Inhaled or topical steroids and adrenal replacement
doses > 10 mg/day prednisone equivalents are permitted in the absence of active
autoimmune disease.

- Patients who are positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis
C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection.

- Patients with a known history of testing positive for human immunodeficiency virus
(HIV) or known acquired immunodeficiency syndrome (AIDS).

- Patients who have received prior external beam radiation therapy to the liver.

- Patients who have clinical evidence of ascites or are in clinical liver failure.

- Patients who are known to have greater than 20% lung shunting of the hepatic artery
blood flow determined by Technetium microaggregated albumin (MAA) scan (if conducted
prior to study enrollment).

- Patients who have had a standard of care pre-assessment angiogram that demonstrates
abnormal vascular anatomy that would result in significant reflux of hepatic arterial
blood to the stomach, pancreas or bowel.

- Patients with known portal vein thrombosis.

- Patients with untreated brain metastases or leptomeningeal metastases will be
excluded. Patients with brain metastases are eligible if metastases have been treated
and there is no magnetic resonance imaging (MRI) evidence of progression for at least
4 weeks after treatment is complete and within 28 days prior to the first dose of
nivolumab administration. There must also be no requirement for immunosuppressive
doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2
weeks prior to study drug administration.

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

- Patients who are pregnant or breastfeeding will be excluded from the study due to the
potential teratogenic or abortifacient effects that may result from nivolumab or Y-90
Theraspheres. Because there is an unknown, but potential risk for adverse events in
nursing infants secondary to treatment of the mother with nivolumab and Y-90,
breastfeeding should be discontinued if the mother is treated with nivolumab and Y-90.
These potential risks may also apply to other agents used in this study.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with nivolumab. In addition, these
subjects are at increased risk of lethal infections when treated with
immunosuppressive agents. Screening HIV testing is not required.