Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Trastuzumab

Pertuzumab

Antineoplastic Agents, Immunological

Blood specimens tested for circulating tumor cells followed by systemic treatment based on assay results with either trastuzumab or pertuzumab

Patients with HER2-negative metastatic breast cancer will be identified, and blood specimens will be obtained from each participant. The PRO Onc Assay will be performed on CTCs isolated from these specimens. When clinically indicated, fine needle aspiration biopsy will also be obtained and submitted for the PRO Onc Assay.

PRO Onc Assay and Treatment

8 mg/kg IV loading dose, followed by 6 mg /kg IV every 3 weeks until progressive disease or unacceptable toxicity with evaluations performed every 8 weeks

840 mg IV loading dose, followed by 420 IV every 3 weeks until progressive disease or unacceptable toxicity with evaluations performed every 8 weeks

John D. Hainsworth, M.D.

This trial will evaluate the clinical significance of the PRO Onc assay and will assess the efficacy of HER2-targeted therapy in patients with HER2-negative breast cancer who have been identified as having HER2 overexpression/activation by the PRO Onc Assay.

This two-part trial is designed to evaluate the clinical significance of the PRO Onc assay when used in patients with metastatic HER2-negative breast cancer. The first part of this study will determine the incidence of HER overexpression/activation, as determined by the PRO Onc assay, in patients previously judged to have HER2-negative breast cancer by FISH analysis. Blood specimens will be obtained from patients with HER2-negative breast cancer; CTCs will then be isolated and tested for HER2 overexpression/activation using the PRO Onc Assay. When clinically indicated, fine needle aspiration biopsy will also be obtained and submitted for the PRO Onc Assay. If the incidence of HER2 overexpression/activation, as determined by the PRO Onc Assay, is \>10%, the study will proceed to Part 2. Part 2 of this study will assess the efficacy of HER2-targeted therapy in a group of patients with HER2-negative breast cancer who are identified as having HER2 overexpression/activation by the PRO Onc Assay. Patients will be treated with either trastuzumab or pertuzumab. Patients who progress during the first 8 weeks will have HER2-targeted treatment discontinued and will be removed from study. After 8 weeks, patients who have stable disease will be allowed to add chemotherapy to HER2-targeted therapy. Patients who have an objective response to single-agent, HER2-targeted therapy after 8 weeks will continue single-agent therapy.

Use of PRO Onc Assay to Assess HER2 in Patients With Metastatic Breast Cancer

Use of the PRO Onc Assay to Assess HER2 Overexpression and Activation in Patients With Metastatic Breast Cancer Whose Tumors Are HER2-Negative by Standard FISH Testing

The percentage of HER2-negative metastatic breast cancer (MBC) patients having an objective benefit from treatment per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Includes patients with HER2 overexpression/activation as detected by PRO Onc Assay.

The percentage of patients having an objective benefit from treatment per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Includes patients with HER2 overexpression as identified by the PRO Onc Assay.

The percentage of patients with HER2 activation (no overexpression) as identified by the PRO Onc Assay who experience an objective benefit from treatment, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Includes patients with HER2-negative metastatic breast cancer (MBC) as determined by FISH testing.

Percentage of HER2-negative MBC patients (identified by FISH testing) having CTCs present in blood specimens.

Prometheus Laboratories

Genentech, Inc.

SCRI Development Innovations, LLC

Includes all patients with HER2 overexpression/activation (as identified by the PRO Onc Assay) who received study treatment

All Treated Patients

Patients Treated

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Excludes patients with no circulating tumor cells for the PRO Onc Assay

John D. Hainsworth, MD

HER2 overexpressed

HER2 activated

HER2 overexpressed and activated

No HER2 overexpression/activation detected

All Patients Evaluated by PRO Onc Assay

Part 1: The Incidence of HER2 Overexpression/Activation as Measured by the PRO Onc Assay

Part II: Objective Response Rate of HER2-negative Metastatic Breast Cancer (by FISH Testing)

All Patients

Includes all patients with blood drawn and analyzed for CTCs

Part I: The Incidence of Isolation of Circulating Tumor Cells (CTCs) From Blood Specimens

Includes patients with HER2 overexpression detected by the PRO Onc Assay

Part II: Objective Response Rate of Trastuzumab Therapy

Includes patients with only HER2 activation (no overexpression) as detected by the PRO Onc Assay

Part II: Objective Response Rate of Pertuzumab Therapy

Patients Enrolled and Blood Collected

Patients Evaluated by PRO Onc Assay

Pts w/ HER2 Overexpression/Activation

Treatment Per Protocol

Symptoms and General Pathology

Neoplasm Metastasis

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

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Use of PRO Onc Assay to Assess HER2 in Patients With Metastatic Breast Cancer	NCT01048099	Breast Cancer	PRO Onc Assay a... Trastuzumab Pertuzumab	18 Years -	SCRI Development Innovations, LLC
A Pharmacokinetic and Randomized Trial of Neoadjuvant Treatment With Anastrozole Plus AZD0530 in Postmenopausal Patients With Hormone Receptor Positive Breast Cancer	NCT01216176	Breast Cancer	Anastrozole AZD0530 (saraca... Placebo	18 Years -	University of Miami

Spots Global Cancer Trial Database for her negative

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