Saracatinib in Treating Patients With Metastatic or Locally Advanced Breast Cancer That Cannot Be Removed By Surgery

Study Overview
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Brief Summary
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This phase II trial is studying saracatinib to see how well it works in treating patients with metastatic or locally advanced breast cancer that cannot be removed by surgery. Saracatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the disease control rate of AZD0530 (saracatinib) in patients with metastatic breast cancer. SECONDARY OBJECTIVES: I. To estimate the efficacy of AZD0530 in terms of overall response rate (complete and partial response) and progression free survival. II. To describe the toxicity profile of AZD0530 in this patient population. III. To prospectively explore changes in circulating tumor cells from pre-treatment levels in patients receiving AZD0530. OUTLINE: Patients receive saracatinib orally (PO) on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 4 weeks.

Official Title
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A Phase II Study of AZD0530 in Hormone Receptor-Negative, Metastatic or Unresectable, Locally Advanced Breast Cancer

Conditions
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Estrogen Receptor-negative Breast Cancer, Male Breast Cancer, Progesterone Receptor-negative Breast Cancer, Recurrent Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* Drug: saracatinib
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed carcinoma of the breast Unresectable disease Locally advanced or metastatic (American Joint Committee on Cancer [AJCC] stage IV) disease Estrogen receptor-negative and progesterone receptor-negative breast cancer defined as < 10% expression by immunohistochemistry (IHC) Measurable disease, defined (per Response Evaluation Criteria in Solid Tumors [RECIST]) as ≥ 1 unidimensionally measurable lesion ≥ 20mm by conventional techniques or ≥ 10 mm by spiral computed tomography (CT) scan Measurable target lesions must not be in a previously irradiated field Patients with locally advanced, unresectable disease must have progression of disease following no more than one first-line chemotherapy regimen Patients with evidence of recurrent disease during or within 6 months after adjuvant chemotherapy will be considered to have failed one line of chemotherapy for metastatic disease Human epidermal growth factor receptor 2 (HER2)-positive patients, defined as immunohistochemistry (IHC) 3+ or fluorescence in situ hybridization (FISH) amplification > 2.1, must have received trastuzumab (Herceptin®) in either the adjuvant or metastatic setting and have had recurrence or progression of disease, respectively No known brain metastases Male and female patients eligible Menopausal status not specified Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 (Karnofsky PS 60-100%) Life expectancy > 3 months Absolute neutrophil count ≥ 1,500/mcL Platelet count ≥ 100,000/mcL Hemoglobin > 9 g/dL Total bilirubin normal Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) ≤ 2.5 x institutional upper limit of normal Creatinine normal OR creatinine clearance ≥ 60 mL/min Urine protein creatinine (UPC) ratio must be ≤ 1.0 Patients with a UPC ratio > 1.0 must have a 24-hour urine protein < 1,000 mg to be eligible for study Not pregnant or nursing Women of child-bearing potential and men must use adequate contraception (e.g., hormonal or barrier method of birth control or abstinence) prior to, during, and for 8 weeks after completion of study therapy Able to understand and willing to sign a written informed consent document No history of allergic reactions attributed to compounds of similar chemical or biological composition to AZD0530 No QTc interval ≥ 500 msecs No condition that impairs the ability to swallow AZD0530 tablets, including the following: Gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation Prior surgical procedures affecting absorption Active peptic ulcer disease No intercurrent cardiac dysfunction including, but not limited to, any of the following: Symptomatic congestive heart failure Unstable angina pectoris Uncontrolled cardiac arrhythmia History of myocardial infarction within 6 months of treatment No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements No severe restrictive or obstructive lung disease according to baseline pulmonary function studies including any of the following pulmonary function test (PFT) parameters: Total lung capacity < 60% Forced vital capacity < 50% Forced expiratory volume in one second (FEV_1) < 50% Diffusion capacity of carbon monoxide (DLCO) < 50% Resting room air O_2 saturation < 92% or a decline in O_2 saturation > 4% with exercise Patients with metastatic disease may have received no more than 1 prior chemotherapy regimen No unresolved toxicity ≥ grade 3 from agents received more than 3 weeks earlier No chemotherapy, radiotherapy, or investigational therapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering study No luteinizing hormone-releasing hormone agonists within 4 weeks prior to study entry More than 7 days since prior and no concurrent use of specifically prohibited cytochrome P 450 3A4 (CYP3A4) agents No concurrent megestrol acetate, even when prescribed for appetite stimulation No other concurrent investigational or commercial agents for the treatment of breast cancer No concurrent combination antiretroviral therapy for human immunodeficiency virus (HIV)-positive patients No concurrent megestrol acetate

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (enzyme inhibitor therapy)<br>Patients receive saracatinib PO on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: saracatinib<br> <br> * Other names: AZD0530;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) | DCR defined as complete response (CR), partial response (PR), stable disease (SD) > 24 weeks. Simon's two-stage optimal design was used to estimate the DCR of AZD0530 after 24 weeks of therapy since this design allowed for early termination of the study. Response and progression was evaluated in this study using the Response Evaluation Criteria in Solid Tumors (RECIST) Target lesions: Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started | After 24 weeks of study therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (CR and PR) | Overall Response rate is defined as the sum of the complete response rate and partial response rate. Response and progression was evaluated in this study using the Response Evaluation Criteria in Solid Tumors (RECIST) Target lesions: Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started | From start of treatment to 24 weeks after completion of study treatment | 
| Median Time to Treatment Failure |  | From the start of treatment up to 4 weeks after completion of study treatment |