Reversing Hormone Resistance in Advanced Breast Cancer With Pazopanib

In this trial, the investigators propose to evaluate the role of VEGFR blockade with the
tyrosine kinase inhibitor pazopanib in combination with nonsteroidal aromatase inhibitors
(NSAI) in patients who are progressing or have relapsed on the same NSAI hormone therapy
given for advanced or early stage breast cancer. If this trial demonstrates clinical benefit,
this all oral combination could be tested in both the neoadjuvant and metastatic settings in
a randomized phase II design.

In order to investigate potential factors predicting response or resistance to pazopanib and
NSAIs, several translational studies have been incorporated into this trial.

The prognostic value of circulating tumor cells (CTC) has been demonstrated in several
studies in breast cancer, especially in advanced stage [35-38]. At UCSF in the laboratory of
Dr. John Park, the investigators have demonstrated expertise in the measurement of CTC in
patients with advanced stage breast cancer by IC/FC assay. CTC are first enriched with
immunomagnetic beads coated with EpCAM, then EpCAM+, CD45-, nucleic acid+ cells are detected
by flow cytometry. This technique is highly sensitive and reproducable, and allows sorting of
cells for molecular analysis as well as analysis of cell surface markers[39]. In this trial,
the investigators will collect patient's peripheral blood samples every 4 weeks while on
treatment and follow any reduction of CTC.

The mechanisms of hormonal resistance includes intrinsic and acquired pathways: decreased ER
expression accounts for intrinsic resistance and the increased receptor tyrosine kinase
pathway relates to acquired resistance [40-42]. The investigators plan to analyze the
mutation of PI3K/Akt and deletion of PTEN by sequencing in CTC (depending on numbers of
cells, which in turn determines feasibility), in order to make a preliminary assessment of
potential markers of response to pazopanib.

The tumor microenvironment plays an important role in cancer development and progression.
Clinical studies have revealed that the increased T regulatory cells (Treg), high ratios of
CD4/CD8 T lymphocytes, and extra follicular B cells in primary tumors correlated with worse
overall survival [43-45]. Recently, studies from preclinical models have shown that tumor
associated macrophages (TAM) can promote pulmonary metastases in breast cancer animal models,
and in both the preclinical and clinical settings are associated with worse clinical outcome
[46-48]. TGFβ has been linked to hormonal resistance in breast cancer. The activation of TGFβ
leads to increased regulatory CD4+ T cells and decreased cytotoxic CD8+ T cells in the tumor
microenvironment [49]. A recent study in non-small cell lung cancer suggests that baseline
and post-treatment levels of cytokines, particularly IL-4 and IL-12 correlated with response
to pazopanib[50]. In this study, the investigators will collect patient's serum to monitor
the level of cytokines at baseline and during treatment, the investigators will compare the
change of cytokine level with pazopanib in each patient, and also compare between responders
and non-responders. This information may help us to identify biomarkers that would predict
response to antiangiogenic therapy and to identify possible mechanisms of resistance.

Inclusion Criteria:

1. Subjects must provide written informed consent prior to performance of study specific
procedures or assessments, and must be willing to comply with treatment and follow up.

- Procedures conducted as a part of routine clinical management of the subject (e.g.,
blood count, imaging study) and obtained prior to signed informed consent may be
utilized for Screening or Baseline purposes provided these tests are obtained as
specified in the protocol).

2. Subjects must have measurable or evaluable disease. Disease sites that are evaluable
for progression but not measurable per RECIST guidelines include:

- Bone lesions

- Previously irradiated lesions

- Cutaneous manifestations (non-discreet lesions only)

3. Age ≥ 18 years.

4. Postmenopausal women defined by one of the criteria:

- No spontaneous menses for at least 12 months if the subject is ≥ 50 years old;

- Amenorrheic for at least 12 months if the subject is < 50 years old, with serum
estradiol within the institutional postmenopausal range;

- Bilateral oophorectomy;

- If prior hysterectomy but intact ovaries, must be ≥ 55 years old, or have serum
estradiol within the postmenopausal range;

- If premenopausal, must be on a GnRH agonist (leuprolide or goserelin) with serum
estradiol levels within the institutional postmenopausal range.

5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2.

6. Histologically or cytologically confirmed estrogen receptor (ER) and/or progesterone
receptor (PgR) positive carcinoma of the breast with unresectable, locally advanced
and/or metastatic (AJCC Stage IV) disease.

7. Subjects must have received prior hormonal therapy for the treatment of breast cancer
as follows:

- Progression must be documented while taking a nonsteroidal aromatase inhibitor
including anastrozole or letrozole.

- No more than 2 prior hormonal therapies for metastatic disease.

- If hormonal therapy was administered in the adjuvant setting, subjects must have
received therapy for at least 6 months prior to developing metastatic disease.

Note: A regimen of sequential tamoxifen/AI in the adjuvant setting is considered to be
one therapy

- If hormonal therapy was administered in the metastatic setting, subjects must have
received therapy for at least 3 months prior to progression

8. Subjects whose tumors overexpress ErbB2 are eligible provided that they have
progressed following therapy which included trastuzumab and/or lapatinib.

Note for prior lapatinib: Subjects must have completed therapy with lapatinib at least
7 days prior to the first dose of study drug.

Note for prior trastuzumab: Subjects who received Q3 weekly, Q2 weekly or Q1 weekly
must have completed therapy with trastuzumab at least 3 weeks, 2 weeks or 1 week,
respectively, prior to the first dose of study drug.

9. Adequate hematologic and hepatic function as defined in Protocol Table 1

10. Subjects must have discontinued hormone replacement therapy (HRT) (e.g., conjugated
estrogens tablets, USP or premarin), at least 28 days prior to receiving the first
dose of randomized therapy.

11. Radiotherapy prior to initiation of therapy is allowed to a limited area (e.g.,
palliative treatment for painful bone metastases), if it is not the sole site of
disease. Subjects must have completed treatment at least one week prior to starting
study drugs, and must have recovered from all treatment-related toxicities.

12. Bisphosphonate or RANK ligand inhibitor therapy for bone metastases is allowed.
Prophylactic use of bisphosphonates in subjects without bone disease, except for the
treatment of osteoporosis, is not permitted;

13. Ability to swallow and retain oral medication.

Exclusion Criteria:

1. Prior use of pazopanib

2. Premenopausal levels of estradiol, or ongoing menses (see definitions of menopause
above).

3. Known central nervous system (CNS) metastases or leptomeningeal carcinomatosis.
Screening with CNS imaging studies (computed tomography [CT] or magnetic resonance
imaging [MRI]) is required only if the subject has clinical findings suggestive of CNS
metastasis.

4. History of another active malignancy. Note: Subjects who have had another malignancy
and have been disease-free for 5 years, or subjects with a history of completely
resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are
eligible.

5. Clinically significant gastrointestinal abnormalities which might interfere with oral
dosing, including, but not limited to:

- Malabsorption syndrome

- Major resection of the stomach or small bowel that could affect the absorption of
study drug

- Inflammatory bowel disease

- Ulcerative colitis, or other gastrointestinal conditions with increased risk of
perforation

- History of abdominal fistula, gastrointestinal perforation, or intra abdominal
abscess within 28 days prior to beginning study treatment

6. Presence of uncontrolled infection.

7. Prolongation of corrected QT interval (QTc) >480msecs.

8. History of any one or more of the following cardiovascular conditions within the past
6 months:

- Angioplasty or stenting

- Myocardial infarction

- Unstable angina

- Coronary artery by-pass graft surgery

- Symptomatic peripheral vascular disease

9. Class II, III or IV congestive heart failure, as defined by the New York Heart
Association (NYHA).

10. Use of an investigational agent, including an investigational anti-cancer agent,
within 14 days prior to the first dose of study drug.

11. Prior use of an investigational drug that targets VEGF or VEGF receptors.

12. Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is
progressing in severity.

13. Poorly controlled hypertension (defined as systolic blood pressure (SBP) of ≥140mmHg
or diastolic blood pressure (DBP) of ≥ 90mmHg).

Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to
study entry. Blood pressure must be re-assessed prior to start of study therapy. The
mean SBP/DBP values must be <140/90mmHg (OR 150/90mmHg, if this criterion is approved
by Safety Review Team) in order for a subject to be eligible for the study.

14. History of cerebrovascular accident (CVA), pulmonary embolism or untreated deep venous
thrombosis (DVT) within the past 6 months.

Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulant
agents for at least 6 weeks are eligible.

15. Major surgery or trauma within 28 days prior to first dose of study drug and/or
presence of any non-healing wound, fracture, or ulcer not related to cancer
(procedures such as catheter placement not considered to be major).

16. Evidence of active bleeding or bleeding diathesis.

17. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that
could interfere with subject's safety, provision of informed consent, or compliance to
study procedures