A Phase I Pharmacokinetic and Randomized Phase II Trial of Neoadjuvant Treatment With Anastrozole Plus AZD0530 in Postmenopausal Patients With Hormone Receptor Positive Breast Cancer
A Phase I Pharmacokinetic and Randomized Phase II Trial of Neoadjuvant Treatment With Anastrozole Plus AZD0530 in Postmenopausal Patients With Hormone Receptor Positive Breast Cancer
The investigators propose to conduct a Phase I/randomized Phase II study design in order to test the tolerability and efficacy of AZD0530 (also called saracatinib) when used together with anastrozole in therapy for ER+ and/or PR+, postmenopausal breast cancer. The Phase I pharmacokinetic (PK) cohort of the study (cohort A) in postmenopausal women with metastatic breast cancer 2008-2009 showed initial safety,tolerability and good bioavailability of both drugs and determined the doses for use in the ongoing Phase II trial. In the randomized Phase II cohort of the study (cohort B), postmenopausal women with newly diagnosed, previously untreated ER+, HER2 negative breast cancer that is at least 2 cm or more in diameter by clinical exam or radiology will be randomized to either neoadjuvant treatment with anastrozole plus placebo, or anastrozole in combination with AZD0530 (saracatinib). The Phase II cohort will permit extended assays of tolerability, initial estimates of efficacy, and the investigation of molecular predictors of drug efficacy.
Inclusion Criteria - Phase 1 (Cohort A):
Female patient ≥ 18 years
Patient must be postmenopausal, verified by 1 of the following:
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
Inclusion Criteria - Phase 2 (Cohort B):
Female patient ≥ 18 years
Patient must be postmenopausal, verified by 1 of the following:
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. Patients may have bilateral or multifocal invasive breast cancers. The patient may have concurrent DCIS in either breast but the DCIS will not be measured as part of the study endpoints.
Tumor size ≥ 2 cm
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)
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
Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
Alkaline phosphatase and AST/ALT ≤ 1.5 x upper limit of normal (ULN)
Exclusion Criteria - Phase 1 (Cohort A):
Concurrent therapy with any other non-protocol anti-cancer therapy
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
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 listed in Appendix XI should be excluded from study.
Any evidence of severe or uncontrolled systemic medical or psychiatric 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):