Bevacizumab, Capecitabine, and Oxaliplatin in Treating Advanced Small Intestinal or Ampulla of Vater Adenocarcinoma

PRIMARY OBJECTIVES:

I. To determine the progression-free survival (PFS) at six months for patients with advanced
adenocarcinoma of the small bowel (small intestine) or ampulla of Vater treated with
capecitabine, oxaliplatin (CAPOX) and bevacizumab.

SECONDARY OBJECTIVES:

I. To determine the response rate (RR) for CAPOX and bevacizumab. II. To determine the
overall progression free survival for CAPOX and bevacizumab.

III. To determine the overall survival (OS) for CAPOX and bevacizumab. IV. To determine the
toxicity of CAPOX and bevacizumab.

OUTLINE:

Participants receive oxaliplatin via central venous catheter (CVC) over 2 hours and
bevacizumab intravenously (IV) over 30-90 minutes on day 1. Participants also receive
capecitabine orally (PO) twice daily (BID) on days 1-14. Courses repeat every 21 days in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 10 and 30 days, and then
every 3 months thereafter.

Inclusion Criteria:

- Patients must have histologically confirmed adenocarcinoma of the small bowel or
ampulla of Vater

- Prior adjuvant chemotherapy (including fluorouracil [5-FU], capecitabine, and
oxaliplatin) for the treatment of adenocarcinoma of the small bowel or ampulla of
Vater is allowed if completed >= 52 weeks prior to first dose of study treatment

- Prior capecitabine or 5-FU administered as a radio-sensitizing agent concurrently with
external beam radiotherapy is allowed

- Patients must have metastatic disease

- A minimum of 4 weeks must have elapsed from completion of any prior chemotherapy or
radiotherapy or surgery and the start date of study therapy

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

- Absolute neutrophil count (ANC) >= 1,500/ul

- Platelets >= 100,000/ul

- Total bilirubin =< 1.5 x upper limit of normal (ULN)

- In patients with known Gilbert's syndrome direct bilirubin =< 1.5 x ULN will be
used as organ function criteria, instead of total bilirubin

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 3 x
ULN

- Calculated creatinine clearance (CrCl) > 50 cc/min (calculated using the Cockcroft and
Gault formula)

- Negative serum or urine pregnancy test in women with childbearing potential (defined
as not post-menopausal for 12 months or no previous surgical sterilization), within
one week prior to initiation of treatment

- 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

- The effects of the combination of CAPOX and bevacizumab on the developing fetus are
unknown. For this reason, women of childbearing potential and men must agree to use
adequate contraception (hormonal or barrier method of birth control) prior to study
entry, for the duration of study participation, and for six months following the
completion of therapy. Should a woman become pregnant while participating in this
study, she should inform her treating physician immediately

- Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with oxaliplatin or capecitabine or bevacizumab,
breast feeding must be discontinued

Exclusion Criteria:

- Patients who have received prior chemotherapy for their metastatic disease are
excluded. Chemotherapy if given as a radiation-sensitizer is allowed

- Patients may not be receiving any other investigational agents nor have received any
investigational drug 28 days prior to enrollment

- Known history of dihydropyrimidine (DPD) deficiency

- Peripheral neuropathy of grade 3 or greater by Common Terminology Criteria for Adverse
Events (CTCAE) 4.0

- Gastrointestinal tract disease resulting in an inability to take oral medication or a
requirement for IV alimentation

- Because of the interaction between coumadin and capecitabine, patients taking
therapeutic doses of coumadin-derivative anticoagulants are not eligible. Low-dose
coumadin (e.g. 1 mg PO per day) in patients with in-dwelling venous access devices is
allowed but increased frequency of international normalized ratio (INR) monitoring is
recommended

- Prior treatment with bevacizumab or known hypersensitivity to any component of
bevacizumab

- Inadequately controlled hypertension (defined as systolic blood pressure >140 mmHg
and/or diastolic blood pressure > 90 mmHg)

- Prior history of hypertensive crisis or hypertensive encephalopathy

- Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation)

- New York Heart Association (NYHA) grade II or greater congestive heart failure

- History of myocardial infarction or unstable angina within 6 months prior to day 1

- History of stroke or transient ischemic attack within 6 months prior to day 1.

- Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to day 1

- History of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) within 1 month
prior to day 1

- History of abdominal fistula or gastrointestinal perforation which must have resolved
at least 6 months prior to day 1

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to day 1 or anticipation of need for major surgical procedure during the course
of the study

- Core biopsy or other minor surgical procedure excluding placement of a vascular access
device, within 7 days prior to day 1

- Serious, non-healing wound, active ulcer, or untreated bone fracture

- Proteinuria at screening as demonstrated by either (1) urine protein:creatinine (UPC)
ratio of >= 1.0 or (2) urine dipstick for proteinuria >= 2+ (patients discovered to
have >/= 2+ proteinuria on dipstick urinalysis should undergo a 24 hour urine
collection and must demonstrate =< 1g of protein in 24 hours to be eligible)

- Known central nervous system (CNS) disease, except for treated brain metastasis.
Treated brain metastases are defined as having no evidence of progression or
hemorrhage after treatment and no ongoing requirement for dexamethasone, as
ascertained by clinical examination and brain imaging (magnetic resonance imaging
[MRI] or computed tomography [CT]) during the screening period. Anticonvulsants
(stable dose) are allowed. Treatment for brain metastases may include whole brain
radiotherapy (WBRT), radiosurgery (RS; gamma knife, linear accelerator [LINAC], or
equivalent) or a combination as deemed appropriate by the treating physician

- Patients with CNS metastases treated by neurosurgical resection or brain biopsy
performed within 3 months prior to day 1 will be excluded

- Current, recent (within 4 weeks of the first infusion of this study), or planned
participation in an experimental drug study other than this study

- Pregnancy (positive pregnancy test) or lactation

- Active malignancy, other than superficial basal cell and superficial squamous (skin)
cell, or carcinoma in situ of the cervix, within last five years

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

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, or psychiatric illness/social
situations that would limit adherence with study requirements