Phase I Trial of Radiation Therapy in Patients With Liver Cancers and Impaired Liver Function

Study Groups and Radiation Administration:

If you are found to be eligible to take part in this study, you will be assigned to a dose
level of radiation based on when you join this study and on your screening test results. The
dose level of radiation measures how much radiation the healthy parts of the liver and other
organs can safely receive during radiation therapy. Two (2) dose levels of radiation will be
tested. Three (3) to 6 participants will be enrolled at each dose level. The first group of
participants will receive a standard dose level. The second group will receive either a
higher or lower dose level than the group before it, depending on what side effects are seen.
This will continue until the highest tolerable dose level is found. Up to 10 participants
will receive radiation at the highest dose level that was found in the first part of the
study.

Radiation Therapy:

You will receive radiation therapy up to 5 days a week for a total of either 15 or 25 doses,
based on what the doctor thinks is in your best interest. Each dose of radiation you receive
should take about 5-10 minutes, but the appointment for each dose of radiation will last
about 1 hour. The study doctor can explain in more detail how the radiation will be given.

You may receive chemotherapy as part of your standard care while you are on study if your
regular doctor thinks it is in your best interest.

Study Visits:

One (1) time each week while you are receiving radiation:

- You will have a physical exam.

- Blood (up to 2 teaspoons) will be drawn for routine tests.

- You will be asked to complete the symptom questionnaire in person, over the internet, or
by telephone.

Length of Study Participation:

You will receive radiation therapy for 15 or 25 treatments. You will no longer be able to
receive radiation treatment if the disease gets worse, if intolerable side effects occur, if
the study doctor thinks it is in your best interest, or if you are unable to follow study
directions.

Your participation on the study will be over after the follow-up visits.

Follow-Up Visits:

About 4-8 weeks after you complete radiation therapy, you will return to the clinic for
follow-up visits. You will have follow-up visits every 3 months during the first year (+/- 1
month) after radiation therapy, and every 4 months (+/- 1 month) in the second year after
radiation therapy. If the disease gets worse or you start another therapy you will have
follow-up visits every 6 months (+/1 month) for up to 2 years. At each visit you will have
the following tests and procedures:

- You will have a physical exam.

- Blood (up to 2 teaspoons) will be drawn for routine tests.

- You will have an MRI, CT scan, and/or positron emission tomography (PET)/CT to check the
status of the disease.

- Each week, you will fill out the symptoms questionnaire during the follow-up period in
person, over the internet, or by telephone. This questionnaire should take about 10
minutes.

This is an investigational study. Radiation therapy is delivered using FDA-approved and
commercially available methods. Combining advanced radiation therapy techniques with
functional imaging for patients with liver cancer and with decreased liver function is
considered investigational.

Up to 88 participants will be enrolled in this study. All will take part at MD Anderson.

Inclusion Criteria:

1. Diagnosis of hepatocellular carcinoma, cholangiocarcinoma, or liver metastasis from
any histology

2. Patients may have single or multinodular tumors

3. There is no specific tumor size cut-off for this protocol. However, the radiation
treatment plan must meet the protocol's dose constraints.

4. Age 18 or older

5. Compromised liver function as defined by any of the following Cohorts: a. Cohort 1:
Advanced cirrhosis group; *Borderline Child-Pugh Class A6, *Child-Pugh Class B, *The
patients in this advanced cirrhosis group must have at least 400 ml of functional
liver, as estimated on either diagnostic imaging (CT or MRI) or SPECT/CT with Tc-99m
sulfur colloid. There is no upper limit on the functional liver volume for these
patients; b. Cohort 2: Low functional liver volume without underlying chronic liver
disease; *Previous irinotecan or oxaliplatin chemotherapy, *Previous liver
resection(s), *These patients must have at least 400 ml of functional liver, as
estimated by either diagnostic imaging computed tomography or magnetic resonance
imaging (CT or MRI) or SPECT/CT with Tc-99m sulfur colloid. There is no upper limit on
the functional liver volume for these patients. (continued to criteria #6)

6. c. Cohort 3: History of of prior liver-directed radiation therapy with either
fractionated EBRT, SBRT or Y90 RE.The interval between prior EBRT and re-irradiation
on protocol should be equal to or greater than 12 months. The interval between prior
Y90 RE and re-irradiation on protocol should be equal to or greater than 6 months.
*Cirrhosis group: i. Child-Pugh Class A5; ii. Borderline Child-Pugh Class A6; iii. The
patients in this group must have at least 400 ml of functional liver, as estimated on
either diagnostic imaging (CT or MRI) or SPECT/CT with Tc-99m sulfur colloid. There is
no upper limit on the functional liver volume for these patients. (continued to
criteria #7)

7. *Low functional liver volume without underlying liver disease. i. Previous irinotecan
or oxaliplatin chemotherapy; ii. Previous liver resection(s); iii. These patients must
have at least 400 ml of functional liver, as estimated by either diagnostic imaging
(CT or MRI) or SPECT/CT with Tc-99m sulfur colloid. There is no upper limit on the
functional liver volume for these patients

8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

9. Women of childbearing potential (those who have not undergone a hysterectomy or who
have not been postmenopausal for at least 24 consecutive months) must agree to
practice adequate contraception and to refrain from breast feeding.

10. Prior history of surgical resection, chemotherapy, TACE, and/or radiofrequency
ablation are allowed.

11. Expected survival must be greater than 3 months

12. Patients may receive concurrent capecitabine or sorafenib at the discretion of the
treating physicians

13. Signed study-specific consent form

Exclusion Criteria:

1. Prior liver-directed radiation therapy for patients in Cohorts 1 (advanced cirrhosis
group) or cohort 2 (low functional volume group)

2. Prior Yttrium-90 therapy for patients in cohorts 1 or 2

3. Patients with a Child-Pugh score less than 6 or greater than 9 for radiation naïve
patients with cirrhosis (cohort 1).

4. Child-Pugh score of greater than 6 for patients with cirrhosis who previously received
liver directed radiation (EBRT or Y90 RE) (cohort 3).

5. Unstable angina, and/or symptomatic congestive heart failure requiring hospitalization
within the last 6 months. Transmural myocardial infarction within the last 6 months
prior to study entry.

6. Current evidence of fever or untreated infection

7. Active hepatitis, including but not limited to viral and drug-induced

8. Poorly controlled inflammatory bowel disease

9. Women with a positive pregnancy test

10. Inability to comply with study and/or follow-up procedures

11. Patients with an active second malignancy or prior invasive malignancy unless disease
free for a minimum of 3 years. Non-melanoma skin cancer and previous early prostate
cancer that had a non-rising PSA can be enrolled.