Durvalumab and Tremelimumab in Treating Patients With Microsatellite Stable Metastatic Colorectal Cancer to the Liver

PRIMARY OBJECTIVES:

I. Establish the safety of durvalumab and tremelimumab following radioembolization with
selective internal radiation (SIR)-Spheres in patients with microsatellite stable (MSS)
metastatic colorectal cancer to the liver.

II. Determine the hepatic response rate of SIR-Spheres followed by durvalumab and
tremelimumab in patients with MSS metastatic colorectal cancer to the liver.

SECONDARY OBJECTIVES:

I. Estimate the progression free survival (PFS) and overall survival (OS) of the overall
treated population.

II. Describe the overall response rate of the treated population. III. Describe the
extra-hepatic response in the treated population (abscopal responses).

TERTIARY OBJECTIVES:

I. Describe intra-tumor immune alterations following SIR-Spheres, and following durvalumab
plus tremelimumab in comparison to baseline through serial hepatic metastases biopsies.

II. Describe the immune alterations in the blood following SIR-Spheres and following
durvalumab plus tremelimumab.

OUTLINE:

Patients receive durvalumab intravenously (IV) over 60 minutes and tremelimumab IV over 60
minutes on day 1. Treatment repeats every 4 weeks for up to 4 courses in the absence of
disease progression or unacceptable toxicity. Beginning at week 17, patients receive
durvalumab IV over 60 minutes on day 1. Treatment repeats every 4 weeks for up to 9 courses
in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Documented informed consent of the subject and/or legally authorized representative

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Life expectancy of > 12 weeks

- Hemoglobin >= 9.0 g/dL

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500 per mm^3)

- Platelet count >= 75 x 10^9/L (>= 75,000 per mm^3)

- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 5 x institutional upper limit of normal given that all patients have liver
metastases

- Serum creatinine clearance (CL) > 40 mL/min by the Cockcroft-Gault formula or by
24-hour urine collection for determination of creatinine clearance

- Female subjects must either be of non-reproductive potential (ie, post-menopausal by
history: >= 60 years old and no menses for >= 1 year without an alternative medical
cause; AND/OR history of hysterectomy, AND/OR history of bilateral tubal ligation,
AND/OR history of bilateral oophorectomy) or must have a negative serum pregnancy test
upon study entry

- Subject is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up

- Patients must have received at least one prior line of therapy for the treatment of
metastatic disease with a fluoropyrimidine in combination with oxaliplatin and/or
irinotecan; patients with prior adjuvant therapy who progressed within 6 months of
completion of treatment may be eligible

- Patients must have liver-only metastases or predominant liver metastatic disease

- Patients should have microsatellite stable (MSS) tumor by polymerase chain reaction
(PCR) assay or mismatch repair protein proficient (MMRP) tumor by immunohistochemistry
as confirmed by the presence of MLH1, MSH2, MSH6, and PMS2; the diagnosis of
colorectal cancer should be confirmed by pathology either on the primary tumor or from
a prior biopsy of a metastatic disease site

- Patients should have been identified by their respective physicians as candidates for
radioembolization and scheduled to undergo such a procedure

- Patients should agree to serial liver metastases biopsy pre-treatment,
post-radioembolization, and post-combination immunotherapy

- Patients should have measurable metastatic disease in the liver, defined (for the
purpose of this study) as at least 1 measurable lesion more than 2 cm in size and
readily accessible to ultrasound (US) or computed tomography (CT)-guided biopsy

- Patients should not be deemed candidate for curative hepatic resection

Exclusion Criteria:

- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site) or previous enrollment in the present study

- Participation in another clinical study with an investigational product during the
last 4 weeks

- Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an
anti-CTLA4, including tremelimumab

- History of another primary malignancy except for:

- Malignancy treated with curative intent and with no known active disease >= 2
years before the first dose of study drug and of low potential risk for
recurrence

- Adequately treated non-melanoma skin cancer or lentigo maligns without evidence
of disease

- Adequately treated carcinoma in situ without evidence of disease eg, cervical
cancer in situ

- Receipt of the last dose of chemotherapy or tyrosine kinase inhibitors should be at
least 3 weeks prior to durvalumab and tremelimumab dosing; monoclonal antibodies such
as bevacizumab, ziv-aflibercept, ramucirumab, cetuximab, and panitumumab should be at
least 6 weeks prior to durvalumab and tremelimumab therapy

- Clinical ascites

- Liver involvement by > 50% with metastatic disease determined by the investigator

- Complete portal vein thrombosis on CT scans

- Failure to satisfy minimum criteria of lung shunting (> 20%) or presence of
extrahepatic gastrointestinal activity on microaggregated albumin (MAA) scan or
angiogram that preclude SIR-Spheres

- Prior external beam radiation to the liver

- Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 3
electrocardiograms (ECGs) using Fridericia's correction

- Current or prior use of immunosuppressive medication within 28 days before the first
dose of durvalumab or tremelimumab, with the exceptions of intranasal, topical, and
inhaled corticosteroids or systemic corticosteroids at physiological doses, which are
not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid

- Any unresolved toxicity (> Common Terminology Criteria for Adverse Events [CTCAE]
grade 2) from previous anti-cancer therapy; subjects with irreversible toxicity that
is not reasonably expected to be exacerbated by the investigational product may be
included (e.g., hearing loss, peripherally neuropathy)

- Any prior systemic anti-cancer immunotherapy treatment

- Active or prior documented autoimmune disease within the past 2 years; NOTE: Subjects
with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within
the past 2 years) are not excluded

- Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
ulcerative colitis)

- History of primary immunodeficiency

- History of allogeneic organ transplant

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active
bleeding diatheses including any subject known to have evidence of acute or chronic
hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric
illness/social situations that would limit compliance with study requirements or
compromise the ability of the subject to give written informed consent

- Known history of previous clinical diagnosis of tuberculosis

- History of leptomeningeal carcinomatosis

- Receipt of live attenuated vaccination within 30 days prior to study entry or within
30 days of receiving durvalumab or tremelimumab

- Any condition that, in the opinion of the investigator, would interfere with
evaluation of study treatment or interpretation of patient safety or study results

- Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive
of but not limited to surgery, radiation and/or corticosteroids

- Subjects with uncontrolled seizures

- Patients with symptomatic extrahepatic metastases

- Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 180 days after the last dose of durvalumab + tremelimumab combination
therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the
longer time period

- Known allergy or hypersensitivity to investigational product (IP) or any excipient