A Phase II Study of AZD2171 in Breast Cancer Stage IV (10006202)

PRIMARY OBJECTIVES:

I. Evaluation of the fraction of patients with increased levels of circulating endothelial
cells after 3 weeks of treatment with AZD2171.

II. Estimation of the objective response rate (ORR = CR + PR) among patients with refractory
breast cancer receiving AZD2171.

SECONDARY OBJECTIVES:

I. Estimation of the response/stable disease rate (RSDR = CR + PR + SD). II.
Characterization of the toxicity associated with AZD2171 in this cohort of patients.

III. Analyses to correlate serial quantification of circulating endothelial cells and
circulating tumor cells with traditional clinical endpoints including RR and TTP.

IV. Develop pharmacodynamic measures of AZ2171 activity based on monocyte count and VEGFR-1
phosphorylation within monocytes.

OUTLINE: This is a nonrandomized, open-label, multicenter study.

Patients receive oral AZD2171 once daily for 42 days. Courses repeat every 42 days in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for 3 months.

PROJECTED ACCRUAL: A total of 26 patients will be accrued for this study.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed Breast Cancer, stage IV,
including:

- "Breast neoplasms malignant and unspecified (incl nipple)","Breast and nipple
neoplasms malignant","Breast cancer stage IV","10006202"

- Breast neoplasms malignant and unspecified (incl nipple)","Breast and nipple
neoplasms malignant","Breast cancer recurrent","10006198"

- "Breast neoplasms malignant and unspecified (incl nipple)","Breast and nipple
neoplasms malignant","Inflammatory carcinoma of breast stage IV","10021979"

- 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

- Patients must have refractory breast cancer, defined as overt clinical tumor
progression on most recent treatment with either hormonal therapy, chemotherapy,
and/or trastuzumab therapy; patients with up to 3 prior chemotherapy regimens and
with any number of biological (hormonal, trastuzumab) regimens for metastatic breast
cancer will be eligible

- Life expectancy of greater than 3 months as assessed by the patient's primary
oncologist

- Absolute neutrophil count > 1,500/mcL

- Platelets > 100,000/mcL

- Hemoglobin >= 8 g/dL

- Prothrombin time < institutional upper limit of normal (ULN)

- Total bilirubin =< 1.5 x ULN

- AST(SGOT)/ALT(SGPT) =< 2.5 × ULN

- Creatinine within normal institutional limits

- Urinalysis with < 1+ proteinuria

- Troponin T or I within normal institutional limits

- LVEF >= 45%, as assessed by echocardiogram or nuclear medicine gated study, within 30
days prior to initiating protocol-based treatment

- At present, the potential of AZD2171 for clinically significant drug interactions
involving the CYP isozymes is unknown; however, studies of the agent in rats
indicated possible suppression of CYP1A that may be of biological significance;
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.

- AZD2171 has been shown to terminate fetal development in the rat, as expected for a
process dependent on VEGF signaling; for this reason, women of child-bearing
potential must have a negative pregnancy test prior to study entry; women of
child-bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the
duration of study participation; should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately

- No therapeutic anti-coagulation; the use of low dose warfarin (1-2 mg/day),
intermittent doses of TPA (2 mg x 1), or heparin flushes to prophylax against central
venous catheter-associated clots is acceptable

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy, radiotherapy, or major surgery within 4 weeks (6
weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have
not recovered from adverse events due to agents administered more than 4 weeks
earlier

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

- Patients may not have been previously treated with an anti-angiogenesis agent

- \Patients may not be receiving any medication that may markedly affect renal function
(e.g., vancomycin, amphotericin, pentamidine); these medications will also not be
permitted after the start of the study

- Patients with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse
events; a head CT or MRI must be performed at baseline

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to AZD2171

- Any contraindications/barrier to oral medication

- EKG abnormalities of known clinical significance, such as prolonged QT (mean QTc >
470 msec, with Bazett's correction, in screening electrocardiogram or history of
familial long QT syndrome); an EKG is required for study entry

- Uncontrolled intercurrent illness including, but not limited to hypertension, ongoing
or active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements

- Pregnant women are excluded from this study because AZD2171 is a VEGF inhibitor with
known abortifacient effects; because there is an unknown but potential risk for
adverse events in nursing infants secondary to treatment of the mother with AZD2171,
breastfeeding should be discontinued if the mother is treated with AZD2171

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with AZD2171; appropriate studies will
be undertaken in patients receiving combination antiretroviral therapy when indicated

- Patients at increased risk for compromised LVEF requiring concurrent use of drugs or
biologics with proarrythmic potential; these drugs are prohibited during studies with
AZD2171 (refer to Appendix J for a listing of these agents)

- Patients with a New York Heart Association classification of III or IV are excluded
(NOTE: patients classified as class II are eligible if controlled on medication and
stable with increased monitoring)