Tremelimumab With Chemoembolization or Ablation for Liver Cancer

Background:

Worldwide, hepatocellular carcinoma (HCC) is the fifth most common malignancy with a median
survival of 6-9 months. For patients with advanced disease sorafenib is the only approved
drug and this has limited benefit.

Tremelimumab is a monoclonal antibody against CTLA4. Anti-CTLA4 therapy has been shown to
enhance anti-tumor immunity by blocking tumor-induced immune suppression of cytotoxic T
cells.

Various tumor ablative procedures and techniques have been shown to result in immunogenic
cell death and induction of a peripheral immune response. Both transarterial catheter
chemoembolization (TACE) and radiofrequency ablation (RFA) have been shown to do this, as
well as cryoablation and external beam radiation.

The underlying hypothesis of this study is that the effect of anti-CTLA4 treatment can be
enhanced by TACE or RFA in patients with advanced hepatocellular carcinoma. We will also
evaluate this in the context of cryoablation and radiation in HCC and RFA in
cholangiocarcinoma.

Objective:

To assess the safety and feasibility of combining Tremelimumab with trans-arterial catheter
chemoembolization (TACE) radiofrequency ablation (RFA), or cryoablation in patients with
advanced HCC.

Eligibility:

Histologically or cytologically confirmed diagnosis of HCC.

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

Barcelona Clinic Liver Cancer (BCLC) Stage B and C patients.

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

-INCLUSION CRITERIA:

1. Patients must have histopathological confirmation of hepatocellular carcinoma (HCC) or
(Cohort E only) 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 in
Cohort E). Fibrolammelar variant is also allowed. For cohort E, the term BTC includes
intraor extrahepatic cholangiocarcinoma, gallbladder cancer or ampullary cancer, as
long as there is an intrahepatic component amenable to RFA.

2. Patients must have disease that is not amenable to potentially curative resection,
transplantation or ablation. For Cohorts A, C and D patients must have progressed on,
been intolerant to, or refused prior sorafenib therapy. Cohort E patients must have

received at least one line of chemotherapy for BTC.

3. Disease must be technically amenable to transhepatic arterial chemoembolization
(TACE), radiofrequency ablation (RFA) or cryoablation. Each case will be discussed at
GI tumor board with interventional

radiology. Patients must have evaluable disease.

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

5. Age greater than or equal to 18 years

6. Life expectancy of greater than 3 months.

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: Bili should be less than or equal to 2 times ULN

- Serum albumin, If cirrhosis present: Part of Child Pugh requirement. If no
cirrhosis: albumin should be greater than or equal to 2.5g/dl

- Patients are eligible with ALT or AST up to 5 times ULN.

- creatinine, less than 1.5 times institution upper limit of normal OR

- creatinine clearance greater than or equal to 45 mL/min/1.73 m(2), as calculated
below, 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.

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.

9. Currently receiving immunosuppressive doses of steroids or other immunosuppressive
medications (inhaled and topical steroids are permitted)

10. History of sarcoidosis syndrome

11. Patients should not be vaccinated with live attenuated vaccines within 1 month of
starting Tremelimumab treatment.

12 Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)

13. 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.

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

15. 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 (hormonal or barrier method of birth control; abstinence) prior to study
entry, the duration of study participation and 3 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.

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