A Pharmacokinetic and Randomized Trial of Neoadjuvant Treatment With Anastrozole Plus AZD0530 in Postmenopausal Patients With Hormone Receptor Positive Breast Cancer

Phase 1

Completed

Conditions: Breast Cancer

Interventions: Drug: Anastrozole
Drug: AZD0530 (saracatinib)
Drug: Placebo

Registration Number: NCT01216176

Lead Sponsor: Joyce Marie Slingerland, MD

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 71

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase 1 - Cohort A	AZD0530 (saracatinib)	Dual treatment with 1 mg anastrozole orally once daily together with AZD0530 (saracatinib) 175 mg orally once daily, or as specified per protocol, until disease progression for treatment of metastatic breast cancer
Phase 2 - Cohort B [Anastrozole + AZD0530]	Anastrozole	Dual treatment with 1 mg anastrozole orally once daily together with AZD0530 (saracatinib) 175 mg orally once daily, or as specified per protocol, until disease progression or 4-6 months of treatment completed.
Phase 2 - Cohort B [Anastrozole + AZD0530]	AZD0530 (saracatinib)	Dual treatment with 1 mg anastrozole orally once daily together with AZD0530 (saracatinib) 175 mg orally once daily, or as specified per protocol, until disease progression or 4-6 months of treatment completed.
Phase 2 - Cohort B [Anastrozole + Placebo]	Placebo	Dual treatment with 1 mg anastrozole orally once daily together with Placebo orally once daily, or as specified per protocol, until disease progression or4-6 months of treatment completed.
Phase 1 - Cohort A	Anastrozole	Dual treatment with 1 mg anastrozole orally once daily together with AZD0530 (saracatinib) 175 mg orally once daily, or as specified per protocol, until disease progression for treatment of metastatic breast cancer
Phase 2 - Cohort B [Anastrozole + Placebo]	Anastrozole	Dual treatment with 1 mg anastrozole orally once daily together with Placebo orally once daily, or as specified per protocol, until disease progression or4-6 months of treatment completed.

Primary Outcome Measures

Name	Time	Method
Phase I Cohort A: Maximum Tolerated AZD0530 Daily Dose Used in Combination With Daily Oral Anastrozole	Cycle 1: Days 1 - 28	To identify a well tolerated dose of AZD0530 (saracatinib) that can be used together with anastrozole in the Phase 2 trial with tolerable toxicity and PK, subjects were followed as AEs recorded and evaluated and drug concentrations were in the therapeutic range.
Phase II - Cohort B: Compare Treatment Groups (AZD0530 + Anastrozole Versus Anastrozole With Placebo) With Respect to Clinical Response	Baseline, cycle 6	Clinical response is defined as percentage change in tumor size calculated from bi-dimensional clinical tumor measurement at diagnosis and on completion of neoadjuvant treatment. The mean reduction in tumor size ( +/-SD) will be derived form the change in largest tumor dimension ( RECIST) and by calculated tumor volume

Secondary Outcome Measures

Name	Time	Method
Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo	From day 1 of treatment until a maximum of 6 months of treatment	Cinically significant AEs defined as clinically significant changes in the patient's symptoms, physical examination and clinical laboratory results are reported as toxicity for AZD0530 (saracatinib) given with anastrozole and for anastrozole given with placebo
Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole	0 hrs, 6 hrs, 12 hrs, 24hrs, 48 hrs, 72 hrs, 8 days, 15 days, 22 days after first dose of AZD0530	Summarized as mean plasma concentrations (ng/ml) of each drug (AZD0530 (saracatinib) and Anastrozole) after exposure to dual therapy.
Phase 1-Cohort A: Peak Concentration of Each Study Drug ( AZD0530 (Saracatinib) and Anastrozole)	0 hrs, 6 hrs, 12 hrs, 24hrs, 48 hrs, 72 hrs, 7 days, 14 days, 21 days after first dose of AZD0530	Summarized as the geometric means and standard deviations for the corresponding for peak plasma concentration of each study drug ( AZD0530 (saracatinib) and anastrozole) after exposure
Phase II Cohort B: Change in Tumor Size by Comparison of Serial MRI	Baseline to 10 weeks;and baseline to 6 months	MRI will be used to compare tumor size at baseline and at 10 weeks. MRI will also be used to compare tumor size at baseline and after completion of 6 months of study medication or disease progression.
Phase II - Cohort B: Number of Participants With Pathologic Complete Response (pCR)	At completion of 4-6 cycles of therapy or after disease progression	A pathologic complete response will be defined as the absence of viable tumor cells in the resected specimen, as determined by standard histologic examination. All specimens will be reviewed by a central pathologist to determine pathologic response.
Phase II - Cohort B: The Number of Participants Achieving Clinical Benefit Defined as Complete Response (CR), or Partial Response (PR) or Stable Disease (SD)	At the end of neoadjuvant therapy	Based on physician measurement of tumor size and by MRI measurements of tumor volume using RECIST criteria
Phase II - Cohort B: To Report the Pharmacokinetics (Mean Blood Levels of Drug) of AZD0530 (Saracatinib) and Anastrozole	Day 28, 56, 84	Blood draws at protocol-specified timepoints to determine mean blood levels of drug for each of AZD0530 and Anastrozole.