Neoplasms

Symptoms and General Pathology

All Conditions

Skin and Connective Tissue Diseases

Neoplasm Metastasis

Breast Neoplasms

Breast Diseases

Skin Diseases

All Drugs and Chemicals

Antineoplastic Agents

Hormones

Estrogens

Anastrozole

Aromatase Inhibitors

Progesterone

Saracatinib

Antineoplastic Agents, Hormonal

Enzyme Inhibitors

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormone Antagonists

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

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.

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.

AZD0530 (saracatinib)

Placebo

Joyce Slingerland, MD

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.

A Pharmacokinetic and Randomized 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

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.

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

Summarized as mean plasma concentrations (ng/ml) of each drug (AZD0530 (saracatinib) and Anastrozole) after exposure to dual therapy.

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

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.

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.

Based on physician measurement of tumor size and by MRI measurements of tumor volume using RECIST criteria

Blood draws at protocol-specified timepoints to determine mean blood levels of drug for each of AZD0530 and Anastrozole.

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

Stanford University

Joyce Marie Slingerland

Professor

Dual treatment with 1 mg anastrozole orally once daily together with AZD0530 175 mg orally once daily, or as specified per protocol, until disease progression for treatment of metastatic breast cancer

Anastrozole

AZD0530

Phase 1 - Cohort A

Dual treatment with 1 mg anastrozole orally once daily together with AZD0530 175 mg orally once daily, or as specified per protocol, until disease progression or 4-6 months of treatment completed.

Anastrozole

AZD0530

Phase 2 - Cohort B [Anastrozole + AZD0530]

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.

Anastrozole

Placebo

Phase 2 - Cohort B [Anastrozole + Placebo]

Total

Age, Categorical

Sex: Female, Male

Race/Ethnicity

Race/Ethnicity, Customized

For the Phase 1 cohort, all 12/12 planned subjects were accrued. Of the planned 60 subjects for Phase 2, 59 subjects were accrued. One was removed from study within a few days ( MD discretion) and is not included in subsequent analysis.

Joyce Slingerland MD PhD FCRP(C)

anastrozole

saracatinib

Phase I Cohort A: Maximum Tolerated AZD0530 Daily Dose Used in Combination With Daily Oral Anastrozole

Max clinical diameter % change

Clinical tumor volume% change

Of 59 subjects, 2 (one/arm)tumors were not palpable at baseline; 1 was removed at MD discretion; 8 removed due to AEs . 48 (30+18) completed 4 mo of therapy and were evaluable for clinical response. Subjects completing 4 months were permitted to go tor surgery. At 24 weeks 19 dual and 16 monotherapy remained evaluable for clinical tumor size.

Phase II - Cohort B: Compare Treatment Groups (AZD0530 + Anastrozole Versus Anastrozole With Placebo) With Respect to Clinical Response

AZD0530 - Cycle 1: 0 hrs

AZD0530 - Cycle 1: 6 hrs

AZD0530 - Cycle 1: 12 hrs

AZD0530 - Cycle 1: 24 hrs

AZD0530 - Cycle 1: 48 hrs

AZD0530 - Cycle 1: 72 hrs

AZD0530 - Day 8

AZD0530 - Day 15

AZD0530 - Day 22

Anastrozole - Day 1: 0 hrs

Anastrozole - Day 1: 6 hrs

Anastrozole - Day 1: 12 hrs

Anastrozole - (24 hrs)

Anastrozole - (48 hrs)

Anastrozole - (72 hrs)

Anastrozole - Day 8

Anastrozole - Day 15

Anastrozole - Day 22

Dual treatment with 1 mg anastrozole orally once daily given for 7 days followed by anastrozole 1 mg orally once daily together with AZD0530 175 mg orally once daily, or as specified per protocol, until disease progression for treatment of metastatic breast cancer.

Anastrozole

AZD0530

Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole

AZD0530 (saracatinib) ng/ml

anastrozole ng/ml

Phase 1-Cohort A: Peak Concentration of Each Study Drug ( AZD0530 (Saracatinib) and Anastrozole)

MRI RECIST % change 10 weeks

MRI tumor volume % change 10 weeks

MRI RECIST % change 6 months

MRI tumor volume % change 6 months

Of 59 subjects, 1 was removed at MD discretion; 8 removed due to AEs. Of the remaining 50 (31 dual + 19 mono), all had MRI at 10 weeks. 3 dual and 1 mono had disease progression and no further MRIs. 7 out of 28 (dual) \& 2 out 18 (mono) completing 4 months, had end of study MRI at wk 18; 21 ( dual) and 16 (mono) had a final MRI at 24 weeks .

Phase II Cohort B: Change in Tumor Size by Comparison of Serial MRI

Phase II - Cohort B: Number of Participants With Pathologic Complete Response (pCR)

Complete Response

Partial Response

Stable Disease

Disease Progression

8 patients were removed from the study due to adverse events

Phase II - Cohort B: The Number of Participants Achieving Clinical Benefit Defined as Complete Response (CR), or Partial Response (PR) or Stable Disease (SD)

Anastrozole - Day 28

Anastrozole - Day 56

Anastrozole - Day 84

AZD0530 - Day 28

AZD0530 - Day 56

AZD0530 - Day 84

PK assays of AZD0530 could not be completed for all participants due to technical problems with the assay protocol

Phase II - Cohort B: To Report the Pharmacokinetics (Mean Blood Levels of Drug) of AZD0530 (Saracatinib) and Anastrozole

Anemia

Neutropenia

Thrombocytopenia

Fatigue

Rash

Alopecia

Hot Flashes

Anorexia

Diarrhea

Alanine aminotransferase increased

Alkaline phosphatase increased

Aspartate aminotransferase increased

Creatinine increased

Hyperbilirubinemia

Flu-like syndrome

Upper Respiratory Infection

Urinary Tract Infection

Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo

Overall Study

Spots Global Cancer Trial Database for phase i for metastatic disease