Ramucirumab for Advanced Pre-Treated Biliary Cancers

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive ramucirumab by
vein over about 60 minutes on Day 1 of each 14-day study cycle.

Study visits:

On or before Day 1 of each cycle:

- You will have a physical exam.

- Blood (about 2 tablespoons) and urine will be collected for routine tests.

On Day 1 of every 2 cycles, blood (about 1 tablespoon) will be drawn for tumor marker
testing. Tumor markers may be related to the status of the disease.

On Day 1 of Cycle 4 and then every 4 cycles after that (Cycles 8, 12, 16, and so on), you
will have a CT scan or MRI to check the status of the disease.

Length of Treatment:

You may continue taking the study drug for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drug if the disease gets worse, if
intolerable side effects occur, or if you are unable to follow study directions.

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

Follow-Up Visits:

Within 10 days after your last dose of study drug:

- You will have a physical exam.

- Blood (about 2 tablespoons) and urine will be collected for routine tests.

- If you have not had one in the last 4 weeks, you will have a CT scan or MRI to check the
status of the disease.

About 30 days after your last dose of study drug, if you have not had one in the last 4
weeks, you will have a CT scan or MRI to check the status of the disease.

If you are not able to come to MD Anderson for the Day 30 follow-up visit, you will be
contacted by phone and asked how you are feeling.

Every 3 months after the 30-day visit, you will be contacted by phone or your medical record
will be checked to monitor your health.

Inclusion Criteria:

1. Patient must have cholangiocarcinoma, gallbladder cancer or adenocarcinoma on liver
biopsy with clinical features consistent with biliary primary/ cholangiocarcinoma.

2. Metastatic or unresectable disease documented on diagnostic imaging studies.

3. Must have received at least one regimen containing gemcitabine chemotherapy.

4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1.

5. The patient has adequate hepatic function as defined by a total bilirubin =/<1.5 mg/dL
(25.65 μmol/L), and aspartate transaminase (AST) and alanine transaminase (ALT) =/<
3.0 times the upper limit of normal (ULN; or 5.0 times the ULN in the setting of liver
metastases).

6. The patient has adequate hematologic function, as evidenced by an absolute neutrophil
count (ANC) =/>1000/µL, hemoglobin =/>9 g/dL (5.58 mmol/L), and platelets
=/>100,000/µL.

7. The patient does not have: a. Cirrhosis at a level of Child-Pugh B (or worse) or; b.
Cirrhosis (any degree) and a history of hepatic encephalopathy or clinically
meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined
as ascites from cirrhosis requiring diuretics or paracentesis.

8. The patient has adequate renal function as defined by a serum creatinine =/<1.5 times
the ULN, or creatinine clearance (measured via 24-hour urine collection) =/>40
mL/minute (that is, if serum creatinine is >1.5 times the ULN, a 24-hour urine
collection to calculate creatinine clearance must be performed).

9. The patient's urinary protein is urinalysis (UA; if urine dipstick or routine analysis is >/=2+ (>/=100-300 mg/dl), a
24-hour urine collection for protein must demonstrate <1000 mg of protein in 24 hours
to allow participation in this protocol).

10. The patient must have adequate coagulation function as defined by International
Normalized Ratio (INR) =/<1.5 and a partial thromboplastin time (PTT) (PTT/aPTT) < 1.5
x ULN.). Patients on full-dose anticoagulation must be on a stable dose (minimum
duration 14 days) of oral anticoagulant or low molecular weight heparin. If receiving
warfarin, the patient must have an INR =/<3.0 and no active bleeding (that is, no
bleeding within 14 days prior to first dose of protocol therapy) or pathological
condition present that carries a high risk of bleeding (for example, tumor involving
major vessels or known varices).

11. Because the teratogenicity of ramucirumab is not known, the patient, if sexually
active, must be postmenopausal, surgically sterile, or using effective contraception
(hormonal or barrier methods).

12. Female patients of childbearing potential must have a negative serum pregnancy test
within 7 days prior to enrollment.

13. Patients must sign an Informed Consent and Authorization indicating that they are
aware of the investigational nature of this study and the known risks involved.

14. Patient is =/> 18 years of age on the day of consenting to the study.

Exclusion Criteria:

1. The patient has experienced any Grade 3-4 GI bleeding within 3 months prior to
enrollment.

2. Prior therapy with any agent targeting the VEGFR pathway to include bevacizumab,
pazopanib, and other anti-angiogenesis inhibitors.

3. The patient has a history of deep vein thrombosis, pulmonary embolism, or any other
significant thromboembolism, including portal venous thrombosis (venous port or
catheter thrombosis, incidental pulmonary embolism diagnosed on imaging studies or
superficial venous thrombosis are not considered significant) during the 3 months
prior to randomization.

4. The patient has experienced any arterial thromboembolic events, including but not
limited to myocardial infarction, transient ischemic attack, cerebrovascular accident,
or unstable angina, within 6 months prior to enrollment.

5. The patient has uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or
> 100 mmHg diastolic for >4 weeks) despite standard medical management.

6. The patient has a serious or non-healing wound, ulcer, or bone fracture within 28 days
prior to enrollment.

7. The patient has undergone major surgery within 28 days prior to enrollment, or
subcutaneous venous access device placement within 7 days prior to enrollment.

8. The patient is receiving chronic antiplatelet therapy, including aspirin, nonsteroidal
anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others),
dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose
325 mg/day) is permitted.

9. The patient has elective or planned major surgery to be performed during the course of
the clinical trial.

10. The patient is pregnant or breast-feeding.