Study of Biweekly Capecitabine Dosing With Bevacizumab for the Treatment of Metastatic Breast Cancer Based Upon the Norton-Simon Mathematical Model

A. Primary Objectives:

• To estimate the efficacy of every other week capecitabine and bevacizumab in patients with
metastatic breast cancer in terms of overall response rate (complete response (CR) + partial
response (PR)) when administered at the MTD of capecitabine determined by the phase I
portion of this trial.

B. Secondary Objectives:

- To estimate secondary efficacy endpoints of this combination including clinical benefit
(CR+PR+SD > 6 months), time to tumor progression (TTP), progression free survival (TTP)
and duration of response.

- To evaluate toxicity rates associated with this capecitabine schedule in combination
with bevacizumab using the NCI CTC (version 3) and the Hand-Foot Syndrome Grading Scale
developed by Roche Laboratories, Inc.

- To evaluate the pharmacogenetics of capecitabine in breast cancer patients by assessing
the impact of specific candidate SNPs on toxicity and/or response.

Inclusion Criteria:

- Patient (male or female) with diagnosis of invasive adenocarcinoma of the breast
confirmed at MSKCC either by histology or cytology.

- Clinical evidence of metastatic breast cancer, non-amenable to surgery or radiation
therapy with curative intent.

- Presence of at least one measurable metastatic lesion according to the RECIST
criteria which has not been irradiated (i.e. newly arising lesions in previously
irradiated areas are accepted). Ascites, pleural effusion, and bone metastases are
not considered measurable. Minimum indicator lesion size: greater than or equal to 10
mm measured by spiral CT or greater than or equal to 20 mm measured by conventional
techniques.

- Any number of prior endocrine or biologic therapies is permitted on this trial. In
addition, patients may be untreated in the metastatic setting or have received any
number of prior cytotoxic regimens. All previous chemotherapy must have been
discontinued at least 3 weeks prior to study entry. All acute toxic effects
(excluding alopecia or neurotoxicity) of any prior therapy must have resolved to NCI
CTC (Version 3) Grade less than or equal to 1.

- Endocrine therapy with an aromatase inhibitor, SERM (ie, tamoxifen) or fulvestrant is
permitted within 4 weeks of study entry, however concurrent therapy with these drugs
is not acceptable.

- ECOG performance status of 0, 1 or 2.

- Patients must be either HER2-negative or HER2-positive and no longer a candidate for
trastuzumab therapy. HER2-negative is defined as 0 or 1+ staining on
immunohistochemistry or FISH negative for gene amplification. HER2-positive is
defined as 3+ staining on immunohistochemistry or FISH positive for gene
amplification.

- Age greater than or equal to 18 years old.

- Baseline laboratory data within the following limits:

- Absolute neutrophil count (ANC) >1.5 x 10^9/L

- Platelets > 100 x 10^9/L

- Estimated creatinine clearance greater than or equal to 50 ml/min by -
Cockcroft-Gault equation

- Total serum bilirubin <1.5 x upper normal limit

- ALT, AST < 2.5x upper normal limit (or <5x upper normal limit in the case of liver
metastases)

- Alkaline phosphatase < 2.5x upper normal limit (or >5x upper normal limit in the case
of liver metastases or >10x upper normal limit in the case of bone disease)

- Serum or urine pregnancy test for females of childbearing potential Negative within
14 days of starting treatment

Exclusion Criteria:

- Pregnant or nursing women may not participate. Patients of reproductive potential may
not participate unless they have agreed to use an effective method of contraception
and to continue contraception for 30 days from the date of the last study drug
administration. Postmenopausal woman must be amenorrheic for at least 12 months to be
considered of nonchildbearing potential.

- Life expectancy < 3 months.

- Serious, uncontrolled, concurrent infection.

- Any prior fluoropyrimidine therapy with the exception of adjuvant administration.
Adjuvant fluoropyrimidine containing therapy must be completed at least 6 months
prior to enrollment.

- Prior severe reaction to fluoropyrimidine therapy, or known hypersensitivity to
5-fluorouracil. A history of DPD deficiency will exclude patients from the trial.

- Completion of previous chemotherapy regimen <3 weeks prior to the start of study
treatment.

- Prior adjuvant hormonal therapy is permitted. Use of an aromatase inhibitor,
anti-estrogen or fulvestrant must be discontinued prior to treatment start.

- Biologic therapy (eg, bevacizumab,trastuzumab) for the treatment of metastatic
disease must be discontinued >3 weeks from the start of protocol treatment.

- HER2-positive patients who are candidates for treatment with trastuzumab are excluded
from this trial as the concurrent use of trastuzumab may confound study results.

- History of prior malignancy with the following exceptions: adequately treated basal
cell or squamous cell carcinoma, in situ cervical cancer, adequately treated Stage I
or II cancer from which the patient is currently in complete remission (with no
evidence of disease) for more than five years.

- Non-malignant systemic disease (cardiovascular, renal, hepatic etc) that would
preclude any of the study therapy drugs. Specifically excluded are the following
cardiac conditions:

- Inadequately controlled hypertension (defined as blood pressure of >150/100 mmHg
on antihypertensive medications)

- Any prior history of hypertensive crisis or hypertensive encephalopathy

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

- History of myocardial infarction or unstable angina within 6 months

- History of stroke or transient ischemic attack within 6 months

- Significant vascular disease or symptomatic peripheral vascular disease

- Capecitabine is contraindicated in patients with a creatinine clearance of <30
ml/min.Patients with a creatinine clearance less than 50 ml/minute by Cockroft and
Gault Equation will be excluded from the trial.

- Patients with symptomatic CNS metastases that remain untreated by radiation therapy
are excluded from this trial. The presence of asymptomatic brain metastases or brain
metastases that have been previously irradiated are not grounds for trial exclusion
for the phase I study however, these patients are excluded from the phase II portion
of the trial.

- History of uncontrolled seizures, central nervous system disorders or psychiatric
disability judged by the investigator to be clinically significant, precluding
informed consent, or interfering with compliance of oral drug intake.

- Other severe, acute or chronic, medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration or may interfere with the interpretation of study results. Any of
the above criteria that in the judgment of the investigator would make the subject
inappropriate for entry into this study.

- Presence of uncontrolled gastrointestinal malabsorption syndrome.

- Concurrent use of oral warfarin anticoagulant therapy is not permitted due to serious
drug interactions with capecitabine. Full dose anticoagulation with low molecular
weight heparin or other (non-warfarin) anticoagulant is permitted.

- Unwillingness to give written informed consent or unwillingness to participate or
inability to comply with the protocol for the duration of the study. Willingness and
ability to comply with scheduled visits, treatment plan, laboratory tests and other
study procedures are necessary for participation in this clinical trial.

- Concurrent radiation therapy is not permitted during treatment on protocol.