Durvalumab (MEDI4736) and Tremelimumab and Radiation Therapy in Hepatocellular Carcinoma and Biliary Tract Cancer

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of investigational drugs to learn whether the drugs work in treating a
specific disease. "Investigational" means that the drugs are being studied.

The FDA (the U.S. Food and Drug Administration) has not approved durvalumab for this specific
disease but it has been approved for other uses.

The FDA has not approved tremelimumab as a treatment for any disease.

Both durvalumab and tremelimumab are antibodies (proteins that work with the immune system)
that target proteins produced by the cancer cells. These cancerous proteins suppress the
immune system which allows the cancer cells to grow. The study drugs may target these
cancerous proteins and stop the cancer cells from suppressing the immune system.

The investigators hope that the combination of these study drugs with radiation therapy will
help stop the cancer cells from growing and spreading.

Inclusion Criteria:

- Histologically or cytologically confirmed hepatocellular carcinoma or biliary tract
cancer

- Locally advanced/unresectable or metastatic disease

- Age ≥ 18 years at time of study entry

- ECOG Performance Status ≤ 1

- One previously unirradiated lesion amenable to 8 Gy x 3 radiotherapy based on
dosimetric organ tolerance AND another unirradiated measurable lesion (per irRECIST)
outside of the radiation field

- Immunotherapy-naïve

- Progressed on, be intolerant of, or refused sorafenib [for HCC], second line treatment
and beyond for cholangiocarcinoma or gemcitabine-based chemotherapy for biliary tract
cancer

- The benefits of sorafenib have been discussed with the patient and the patient has
refused treatment with sorafenib.

- Viral status (Hepatitis B and C) must be known. All HBV-positive patients must be on
antiviral medication for viral suppression.

- Patients with concomitant HBV infection must have a confirmed diagnosis of HBV
characterized by the presence of hepatitis B core antibodies, and be sufficiently
suppressed with active antiviral treatment (per local institutional practice)
prior to enrollment to ensure adequate viral suppression (HBV deoxyribonucleic
acid [DNA] <2000 IU/mL).

- Patients with concomitant HCV infection must have confirmed diagnosis of HCV
characterized by the presence of detectable HCV ribonucleic acid (RNA or anti-HCV
antibody upon enrollment.

- Body weight ≥ 30 kg

- Child-Pugh Score of A. A score of B7 is allowed without severe ascites or without
hepatic encephalopathy.

- Adequate organ and marrow function, defined as:

- Hemoglobin ≥ 9 g/dL

- ANC ≥ 1.5 x 10^9/L

- Platelet count ≥75×109/L

- Serum bilirubin ≤2.0× the upper limit of normal (ULN).

- ALT and AST ≤ 3 x institutional ULN

- Albumin > 2.8 g/dL

- INR < 2.0

- Calculated creatinine clearance > 40 mL/min as determined by Cockcroft-Gault
(using actual body weight)

- Males:

--Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)

- Females:

--Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine
(mg/dL)

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

- Female subjects must be either of non-reproductive potential (i.e., post-menopausal by
history: ≥ 50 years old and no menses for ≥1 year without an alternative medical
cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history
of bilateral oophorectomy) or must have a negative serum pregnancy test upon study
entry.

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

Exclusion Criteria:

- Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC

- Prior irradiation to the planned radiation target lesion

- Prior immunotherapy including but not limited to anti-CTLA4, including tremelimumab
anti-PD-1, and anti-PD-L1, including durvalumab

- Concurrent enrollment in another study unless it is an observational (e.g.
non-interventional) study

- Received live attenuated vaccines within 30 days of first dose

- Mean QT interval corrected for heart rate (QTc) ≥ 470 ms using Fredericia's Correction

- History of primary immunodeficiency

- History of solid organ transplantation

- Active or prior documented autoimmune disease within the past 2 years (NOTE: The
following are exceptions to this criterion: Participants with vitiligo or alopecia;
Participants with hypothyroidism (e.g. following Hashimoto syndrome) who are stable on
hormone replacement; Participants with celiac disease controlled by diet alone:
Participants with Grave's disease, or any chronic skin condition not requiring
systemic treatment. Participants without active disease in the last 5 years may be
included but only after consultation with the study physician.)

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

- Prior other malignancy within 2 years (except for in situ disease, which is
permissible)

- History of hypersensitivity to durvalumab, tremelimumab or any excipient

- History of (non-infectious) pneumonitis that required steroids; or evidence of
interstitial lung disease or active, non-infectious pneumonitis

- 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, or psychiatric illness/social situations that would limit
compliance with study requirements or compromise the ability of the subject to give
written informed consent

- Current or prior use of immunosuppressive medication within 28 days before the first
dose of treatment on this protocol, with the exceptions of

- Intranasal and inhaled corticosteroids

- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or equivalent

- Premedication for hypersensitivity reactions (e.g. to CT contrast for scans)

- Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and TB testing in line with
local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients
with a past or resolved HBV infection (defined as the presence of hepatitis B core
antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
for HCV RNA.

- Subjects with uncontrolled seizures

- Female subjects who are pregnant or breast-feeding or male or female patients of
reproductive potential who are not employing an effective method of 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.

- Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria

- Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after
consultation with the Study Physician.

--Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab or tremelimumab may be included only after consultation with
the Study Physician.

- Major surgical procedure (as defined by the Investigator) within 28 days prior to the
first dose of IP. Note: Local surgery of isolated lesions for palliative intent is
acceptable.

- Brain metastases or spinal cord compression. Patients with suspected brain metastases
at screening should have an MRI (preferred) or CT each preferably with IV contrast of
the brain prior to study entry or brain metastases or spinal cord compression unless
the patient is stable (asymptomatic; no evidence of new or emerging brain metastases;
and stable and off steroids and anti-convulsants for at least 14-28 days prior to
start of study treatment). Following radiotherapy and/or surgery of the brain
metastases patients must wait 4 weeks following the intervention to confirm stability.