A Pilot Study of Combined Immune Checkpoint Inhibition in Combination With Ablative Therapies in Subjects With Hepatocellular Carcinoma (HCC) or Biliary Tract Carcinomas (BTC)

BACKGROUND:

- Various tumor ablative procedures and techniques have been shown to result in
immunogenic cell death and induction of a peripheral immune response. The term ablative
therapies applies to trans-arterial catheter chemoembolization (TACE), radiofrequency
ablation (RFA) and cryoablation (CA).

- The underlying hypothesis of this study is that the effect of immune checkpoint
inhibition can be enhanced by TACE, CA and RFA in patients with advanced hepatocellular
carcinoma (HCC) and biliary tract carcinomas (BTC). We have already demonstrated proof
of principle as well as safety and feasibility of this approach with anti-CTLA4 therapy.

- Based on the concept of PDL1-mediated adaptive resistance and the emerging role of PD1
therapy in HCC, we would like to evaluate the combination of tremelimumab and durvalumab
(with ablative therapies) in HCC and BTC.

Objectives:

- To preliminarily evaluate the 6-month progression free survival (PFS) of combining
tremelimumab and durvalumab in patients with advanced HCC (either alone or with cryoablation,
TACE or RFA) and in patients with advanced biliary tract carcinoma (BTC) (either alone or
with cryoablation or RFA).

ELIGIBILITY:

- Histologically or cytologically confirmed diagnosis of HCC or biliary tract carcinoma OR
histopathological confirmation of carcinoma in the setting of clinical and radiological
characteristics which, together with the pathology, are highly suggestive of a diagnosis
of HCC (or biliary tract carcinoma).

- Childs-Pugh A/B7 cirrhosis only is allowed. If patient does not have cirrhosis, this
limitation does not apply.

- Patients must have disease that is not amenable to potentially curative resection,
radiofrequency ablation, or liver transplantation.

DESIGN:

We will evaluate the combination of tremelimumab and durvalumab (with ablative therapies) in
cohorts A1 (HCC; Barcelona clinic liver cancer staging system (BCLC) stage C; N=10), A2 (HCC;
BCLC stages B/C; N=30) and B (BTC; N=30). The patients in cohort A1 and first 10 patients in
cohort B will receive tremelimumab and durvalumab only (i.e. no interventional radiologic
procedures).

- INCLUSION CRITERIA:

1. Patients must have histopathological confirmation of hepatocellular carcinoma
(HCC) or biliary tract carcinoma (BTC) by the Laboratory of Pathology of the NCI
prior to entering this study OR histopathological confirmation of carcinoma in
the setting of clinical and radiological characteristics which, together with the
pathology, are highly suggestive of a diagnosis of HCC (or biliary tract
carcinoma). Fibrolamellar variant is also allowed. The term BTC includes intraor
extrahepatic cholangiocarcinoma, gallbladder cancer or ampullary cancer.

2. Patients must have disease that is not amenable to potentially curative
resection, transplantation or ablation. HCC patients must have progressed on,
been intolerant to, or refused prior sorafenib therapy. Patients with BTC must
have received, been intolerant of or refused at least one line of chemotherapy.

3. Patients must have multiple tumor lesions (at least 2): one for the ablation
procedure and another for evaluation located outside the proposal ablation zone.

4. Disease must be technically amenable to transhepatic arterial chemoembolization
(TACE) (HCC patients only), radiofrequency ablation (RFA), or cryoablation. Each
case will be discussed at GI tumor board with interventional radiology. Patients
must have evaluable disease.

5. If liver cirrhosis is present, patient must have a Child-Pugh A/B7 classification

6. Age 18 years or older

7. ECOG performance status 0-2

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

- leukocytes greater than or equal to 3,000/mcL

- absolute neutrophil count greater than or equal to 1,000/mcL

- platelets greater than or equal to 60,000/mcL

- total bilirubin If cirrhosis present: Part of Child Pugh requirement; If no cirrhosis:
bilirubin should be less than or equal to 2 xULN

- serum albumin If cirrhosis present: Part of Child Pugh requirement; If no cirrhosis:
albumin should be less than or equal to 2.5g/dl

- patients are eligible with ALT or AST up to 5 x ULN.

- creatinine < 1.5x institution upper limit of normal OR creatinine clearance greater
than or equal to 45 mL/min/1.73 m^2 for patients with creatinine levels above
institutional normal

9. Patients must have recovered from any acute toxicity related to prior therapy,
including surgery. Toxicity should be less than or equal to grade 1 or returned to
baseline.

10. Patients must not have other invasive malignancies within the past 5 years (with
the exception of non-melanoma skin cancers, non-invasive bladder cancer or localized
prostate cancer for whom systemic therapy is not required).

11. Patient must be able to understand and willing to sign a written informed consent
document.

12. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they have
been amenorrheic for 12 months without an alternative medical cause. The following
age-specific requirements apply:

- Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal treatments
and if they have luteinizing hormone and follicle-stimulating hormone levels in the
post-menopausal range for the institution or underwent surgical sterilization
(bilateral oophorectomy or hysterectomy).

- Women greater than or equal to 50 years of age would be considered post-menopausal if
they have been

amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments,
had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced
menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral
oophorectomy, bilateral salpingectomy or hysterectomy. 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.

13. Body weight greater than 30kg

EXCLUSION CRITERIA:

1. Patients who have had standard of care chemotherapy, large field radiotherapy, or
major surgery must wait 2 weeks prior to entering the study. For recent experimental
therapies a 28 day period of time must elapse before treatment.

2. Patients who have undergone prior liver transplantation are ineligible.

3. Patients with known brain metastases will be excluded from this clinical trial because
of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.

4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
systemic infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia (excluding insignificant sinus bradycardia and sinus tachycardia)
or psychiatric illness/social situations that would limit compliance with study
requirements.

5. History of chronic autoimmune disease (e.g., Addison s disease, multiple sclerosis,
Graves disease, Hashimoto s thyroiditis, rheumatoid arthritis, hypophysitis, etc.)
with symptomatic disease within the 3 years before randomization. Note: Active
vitiligo or a history of vitiligo will not be a basis for exclusion.

6. Dementia or significantly altered mental status that would prohibit the understanding
or rendering of Information and Consent and compliance with the requirements of the
protocol.

7. Diverticulitis either active or history of within the past 2 years. Note that
diverticulosis is permitted.

8. Active or history of inflammatory bowel disease (colitis, Crohn s), irritable bowel
disease, celiac disease, or other serious, chronic, gastrointestinal conditions
associated with diarrhea. Active or history of systemic lupus erythematosus or Wegener
s granulomatosis. Currently receiving immunosuppressive doses of steroids or other
immunosuppressive medications (inhaled and topical steroids are permitted)

9. History of sarcoidosis syndrome

10. Patients should not be vaccinated with live attenuated vaccines within 30 days of
starting durvalumab or tremelimumab treatment.

11. Has a known history of Human Immunodeficiency Virus (HIV). HIV-positive patients
receiving anti-retroviral therapy are excluded from this study due to the possibility
of pharmacokinetic interactions between antiretroviral medications and tremelimumab.
HIV positive patients not receiving antiretroviral therapy are excluded due to the
possibility that tremelimumab may worsen their condition and the likelihood that the
underlying condition may obscure the attribution of adverse events.

12. History of hypersensitivity reaction to human or mouse antibody products.

13. Pregnancy and breast feeding are exclusion factors. The effects of tremelimumab on the
developing human fetus are unknown. Enrolled patients must agree to use adequate
contraception prior to study entry, the duration of study participation and 6 months
after the end of the treatment. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately.

14. Patients with unhealed surgical wounds for more than 30 days.