Cediranib Maleate and Combination Chemotherapy in Treating Patients With Advanced Biliary Cancers

PRIMARY OBJECTIVES:

I. To determine the response rate to AZD2171 and modified FOLFOX 6 in subjects with advanced
biliary cancers.

SECONDARY OBJECTIVES:

I. To determine overall assessment of toxicity of AZD2171 and modified FOLFOX6. II. To
determine the progression-free survival of subjects with advanced biliary cancers treated
with AZD2171 and modified FOLFOX6.

III. To determine overall survival of subjects with advanced biliary cancers treated with
AZD2171 and modified FOLFOX6.

OUTLINE: This is a multicenter study.

Patients receive oral cediranib maleate once daily on days 1-14 and modified FOLFOX6
comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil
IV over 46 hours on day 1. Courses repeat every 14 days in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year,
every 6 months for 2 years, and then annually thereafter.

Inclusion Criteria:

- Patients with histopathological diagnosis of advanced biliary carcinoma (gallbladder
cancer, cholangiocarcinoma, ampullary cancer) not amenable to conventional surgical
approach are eligible

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as >
20 mm with conventional techniques or as > 10 mm with spiral CT scan

- No patients with untreated brain metastases

- ECOG performance status ≤ 2 (Karnofsky ≥ 60%)

- Life expectancy of greater than 12 weeks

- WBC/leukocytes ≥ 3,000/μL

- Absolute neutrophil count ≥ 1,500/μL

- Platelets ≥ 100,000/μL

- Hemoglobin ≥ 9 g/dL

- Total bilirubin ≤ 3 mg/dL

- AST (SGOT)/ALT (SGPT) ≤ 2.5 times institutional upper limit of normal

- Creatinine within normal institutional limits OR calculated creatinine clearance ≥ 60
mL/min

- No patients with proteinuria not meeting the criteria below; urine sample must be
tested by UPC ratio or by dipstick method within 1 week of starting study treatment;
depending upon the testing method used, the following criteria must be met:

- UPC ratio must be < 1.0; if UPC ratio is ≥ 1.0, a 24-hour urine specimen must be
collected and must demonstrate < 1 g of protein

- Urine dipstick must indicate 0-1+ protein; if dipstick reading is ≥ 2+, a
24-hour urine specimen must be collected and must demonstrate < 1 g of protein

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use adequate contraception (hormonal or barrier method of birth
control; abstinence) before and during study treatment

- Acceptable contraception includes abstinence, oral contraceptives, intra-uterine
device (IUD), diaphragm, Norplant, approved hormone injections, condoms, or
documentation of medical sterilization

- Patients with evidence of heart disease must be NYHA Class I or II

- NYHA Class II patients controlled with treatment are considered at increased
risk for compromised LVEF and will undergo increased cardiac monitoring

- No patients with other active cancers except nonmelanoma skin cancer or carcinoma
in-situ of the cervix

- History of prior cancer is allowed as long as there has been no evidence of
disease within the past 5 years

- No patients with mean QTc > 480 msec (with Bazett's correction) in screening
electrocardiogram or history of familial long QT syndrome

- No patients with uncontrolled hypertension defined as systolic BP ≥ 140 mm Hg or
diastolic BP ≥ 90 mm Hg, with or without anti-hypertensive medication or history of
hypertensive crisis or hypertensive encephalopathy

- Patients with initial BP elevations are eligible once their PI is controlled to
above parameters

- No patients with uncontrolled intercurrent illness including, but not limited to:

- Hypertension (> 140/90 mm Hg)

- Chronic or active infection requiring chronic suppressive antibiotics

- History of or symptomatic congestive heart failure requiring chronic medical
therapy

- NYHA class III or IV heart disease

- Unstable angina pectoris within 180 days prior to starting study treatment

- Myocardial infarction within 180 days prior to study treatment

- Gastroduodenal ulcer(s) determined by endoscopy to be active within 180 days
prior to study treatment

- Serious or non-healing wound, skin ulcers, or bone fracture

- Any significant bleeding that is not related to the primary tumor within 180
days prior to study treatment

- Known bleeding diathesis or coagulopathy

- Paresthesias, peripheral sensory neuropathy > gr. 1 per CTCAE v.4, or peripheral
motor neuropathy ≥ gr. 2 per CTCAE v.4

- Psychiatric illness/social situations that would limit compliance with study
requirements

- No patients with history of TIA or CVA within 180 days prior to study treatment,
symptomatic peripheral ischemia; history of arterial thrombotic event within 180 days
prior to study treatment; GI perforation within 180 days prior to study treatment

- HIV-positive patients on combination antiretroviral therapy are ineligible

- Patients who are chemotherapy naive unless chemotherapy was given as adjuvant
post-surgical treatment and at least 6 months have elapsed since adjuvant
chemotherapy

- No patients who have had major surgical procedures, open biopsies, or significant
traumatic injury within 28 days prior to study treatment

- Chemotherapy for prior cancer is permitted

- Eligibility of patients receiving any medications or substances known to affect or
with the potential to affect the activity or PK of AZD2171 will be determined
following review of their case by the Principal Investigator

- Efforts should be made to switch patients with brain metastases who are taking
enzyme-inducing anticonvulsant agents to other medications

- Patients may not be receiving any other investigational agents nor have participated
in an investigational trial within the past 30 days

- Patients may not be receiving any medication that may markedly affect renal function
(e.g., vancomycin, amphotericin, pentamidine)

- Patients may not be receiving therapeutic doses of Coumadin or equivalent

- No patients requiring drugs with proarrhythmic potential