A Phase I Pharmacokinetic and Randomized Phase II Trial of Neoadjuvant Treatment With Anastrozole Plus AZDO530 in Postmenopausal Patients With Hormone Receptor Positive Breast Cancer

Inclusion Criteria

Inclusion Criteria - Phase 1 (Cohort A):

- Female patient > 18 years

- Patient must be postmenopausal, verified by 1 of the following:

- Bilateral surgical oophorectomy

- No spontaneous menses > 1 year

- No menses for < 1 year with FSH and estradiol levels in postmenopausal range

- Postmenopausal women with primary invasive breast cancer, histologically confirmed by
core needle (or incisional biopsy), whose tumors are estrogen (ER) and/or
progesterone (PgR) positive. Estrogen- and/or progesterone-receptor positive disease
based on 10% or more nuclear staining of the invasive component of the tumor

- Stage IV disease (as defined by the AJCC Staging Manual, 6th Edition, 2002); or
locally relapsed, unresectable disease

- Measurable or evaluable disease according to RECIST criteria (see appendix VII)

- Both HER2-positive and HER2-negative disease (as defined by IHC or by fluorescence in
situ hybridization [FISH]). HER2+ must have had prior treatment with trastuzumab
and/or lapatinib.

- ECOG performance status 0-2 (see appendix VI)

- Patients are suitable candidates for treatment with anastrozole (patients may have
had any prior endocrine therapy or prior chemotherapy for treatment of their disease,
either as adjuvant therapy, or as treatment for advanced disease). There is no
restriction on the number of prior regimens in the phase I cohort A.

- Patient is accessible and willing to comply with treatment and follow-up

- Patient is willing to provide written informed consent prior to the performance of
any study-related procedures

- Required laboratory values

- Absolute neutrophil count > 1.5 x 109/L

- Hemoglobin > 9.0 g/dL

- Platelet count > 100 x 109/L

- Creatinine < 1.5 mg/dL

- Total bilirubin < 1.0 x upper limit of normal (ULN)

- Alkaline phosphatase and AST/ALT within protocol parameters. In determining
eligibility, the more abnormal of the two values (AST or ALT) should be used.

Inclusion Criteria - Phase 2 (Cohort B):

- Female patient > 18 years

- Patient must be postmenopausal, verified by 1 of the following:

- Bilateral surgical oophorectomy

- No spontaneous menses > 1 year

- No menses for < 1 year with FSH and estradiol levels in postmenopausal range

- Postmenopausal women with primary invasive breast cancer, histologically confirmed by
core needle (or incisional biopsy), whose tumors are estrogen (ER) and/or
progesterone (PgR) positive. Estrogen- and/or progesterone-receptor positive disease
based on 10% or more nuclear staining of the invasive component of the tumor

- Stage II (minimum tumor size > 3 cm) or Stage III disease (except inflammatory breast
cancer), as defined by the AJCC Staging Manual, 6th Edition, 2002

- Tumor measurable either by clinical examination, mammography, MRI, or ultrasound

- HER2-negative disease (as defined by fluorescence in situ hybridization [FISH] or by
IHC)

- ECOG performance status 0-1 (see Appendix VI)

- No prior chemotherapy, radiotherapy, or endocrine therapy for invasive or noninvasive
breast cancer

- Patient is accessible and willing to comply with treatment and follow-up

- Patient is willing to provide written informed consent prior to the performance of
any study-related procedures

- Required laboratory values

- Absolute neutrophil count > 1.5 x 109/L

- Hemoglobin > 9.0 g/dL

- Platelet count > 100 x 109/L

- Creatinine < 1.5 mg/dL

- Total bilirubin < 1.0 x upper limit of normal (ULN)

- Alkaline phosphatase and AST/ALT within protocol parameters. In determining
eligibility, the more abnormal of the two values (AST or ALT) should be used.

Exclusion Criteria - Phase 1 (Cohort A):

- Concurrent therapy with any other non-protocol anti-cancer therapy.

- Any agent with estrogenic or putatively estrogenic properties, including herbal
preparations, must be stopped at least one week prior to registration.

- Ongoing, chronic administration of bisphosphonate therapy is allowed so long as
such treatment was ongoing at the time of study entry.

- Current therapy with hormone replacement therapy, or any hormonal agent such as
raloxifene, tamoxifen, or other selective estrogen receptor modulators (agents must
be stopped prior to randomization)

- Presence of neuropathy > grade 2 (NCI-CTC version 3.0) at baseline

- History of any other malignancy within the past 5 years, with the exception of
non-melanoma skin cancer or carcinoma-in-situ of the cervix

- Clinically significant cardiovascular disease (e.g., hypertension [BP > 150/100],
history of myocardial infarction or stroke within 6 months, unstable angina), New
York Heart Association (NYHA) Grade II or greater congestive heart failure, or
serious cardiac arrhythmia requiring medication

- Active, uncontrolled infection requiring parenteral antimicrobials

- The presence of any other medical or psychiatric disorder that, in the opinion of the
treating physician, would contraindicate the use of the drugs in this protocol or
place the subject at undue risk for treatment complications

- A history of a severe hypersensitivity reaction to anastrozole, or AZD0530 or their
excipients

- Evidence of bleeding diathesis or coagulopathy.

- Resting EKG with measurable QTc interval of >480msec at 2 or more time points within
a 24 hr period.

- Since AZD0530 is a substrate and inhibitor of CYP3A4,patients requiring medication
with drugs that are known to significantly modulate CYP3A4 activity or are
metabolized by CYP3A4 should be excluded from study. See Appendix XI. List of
medications which inhibit, induced or utilize the CYP3A metabolic pathway

- Any evidence of severe or uncontrolled systemic conditions (e.g. Severe hepatic
impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease])
or current unstable or uncompensated respiratory or cardiac conditions which make it
undesirable for the patient to participate in the study or which could jeopardize
compliance with the protocol

- Evidence of underlying pulmonary dysfunction as evidenced by oxygen saturation <90%
by pulse oximetry, interstitial pulmonary infiltrates on high resolution CT scan
prior to study entry and/or symptomatic pulmonary (pleural or parenchymal)
metastasis.

Exclusion Criteria - Phase 2 (Cohort B):

- Prior chemotherapy, endocrine therapy or radiotherapy for Stage II or Stage III
breast cancer

- Inflammatory BC, clinically defined as the presence of erythema or induration
involving one-third or more of the breast, or pathologically defined as dermal
lymphatic invasion

- Prior excisional biopsy or complete resection of the primary invasive tumor (prior
sentinel node biopsy allowed)

- Prior ipsilateral radiation therapy for invasive or non-invasive breast cancer

- Bilateral or multifocal invasive breast cancer

- Distant metastasis - Isolated ipsilateral supraclavicular node involvement allowed

- Concurrent therapy with any other non-protocol anti-cancer therapy Any agent with
estrogenic or putatively estrogenic properties, including herbal preparations, must
be stopped at least one week prior to registration

- Current therapy with hormone replacement therapy, or any hormonal agent such as
raloxifene, tamoxifen, or other selective estrogen receptor modulators (agents must
be stopped for two weeks prior to randomization)

- Presence of neuropathy > grade 2 (NCI-CTC version 3.0) at baseline

- History of any other malignancy within the past 5 years, with the exception of
non-melanoma skin cancer or carcinoma-in-situ of the cervix

- Clinically significant cardiovascular disease (e.g., hypertension [BP > 150/100],
history of myocardial infarction or stroke within 6 months, unstable angina), New
York Heart Association (NYHA) Grade II or greater congestive heart failure, or
serious cardiac arrhythmia requiring medication

- Active, uncontrolled infection requiring parenteral antimicrobials

- The presence of any other medical or psychiatric disorder that, in the opinion of the
treating physician, would contraindicate the use of the drugs in this protocol or
place the subject at undue risk for treatment complications

- A history of a severe hypersensitivity reaction to anastrozole, or AZD0530 or their
excipients

- Evidence of bleeding diathesis or coagulopathy

- Resting EKG with measurable QTc interval of >480msec at 2 or more time points within
a 24 hr period.

- Since AZD0530 is a substrate and inhibitor of CYP3A4, patients requiring medication
with drugs that are known to significantly modulate CYP3A4 activity or are
metabolized by CYP3A4 should be excluded from study. See Appendix XI. List of
medications which inhibit, induced, or utilize the CYP3A metabolic pathway.

- Any evidence of severe or uncontrolled systemic conditions (eg. Severe hepatic
impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease])
or current unstable or uncompensated respiratory or cardiac conditions which make it
undesirable for the patient to participate in the study or which could jeopardize
compliance with the protocol

- Evidence of underlying pulmonary dysfunction as evidenced by oxygen saturation <90%
by pulse oximetry, interstitial pulmonary infiltrates on high resolution CT scan
prior to study entry and/or symptomatic pulmonary (pleural or parenchymal) disease.