Breast Cancer
Conditions
Keywords
Breast Cancer, Postmenopausal, Metastatic Phase I ONLY, AZD0530 (saracatinib), Anastrozole, Phase I for metastatic disease, Phase II for newly diagnosed breast cancer, Pharmacokinetic, PK, Hormone Receptor, Estrogen Receptor, Progesterone Receptor, ER+, PR+, HER negative, Aromatase Inhibitors
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.
Interventions
DRUGAnastrozole
DRUGAZD0530 (saracatinib)
DRUGPlacebo
Sponsors
Stanford University
Joyce Marie Slingerland, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
- Phase 1 (Cohort A): * Female patient ≥ 18 years * Patient must be postmenopausal, verified by 1 of the following: * Bilateral surgical oophorectomy * No spontaneous menses \> 1 year * No menses for \< 1 year with FSH and estradiol levels in postmenopausal range. If a study subject under the age of 60 reports prior surgery in which the ovaries were removed and if the operative report cannot be obtained to confirm bilateral salpingo-oophorectomy, the subject will have serum estradiol, LH and FSH drawn to confirm menopausal status prior to study entry * 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 * Absolute neutrophil count ≥ to 1.5 x 10\^9/L * Hemoglobin ≥ to 9.0 g/dL * Platelet count ≥ to 100 x 10\^9/L * Creatinine ≤ 1.5 mg/dL * Total bilirubin ≤ 1.0 x upper limit of normal (ULN) * Alkaline phosphatase and AST/ALT within protocol parameters. In determining eligibility, the more abnormal of the two values (AST or ALT) should be used. Inclusion Criteria - Phase 2 (Cohort B): * Female patient ≥ 18 years * Patient must be postmenopausal, verified by 1 of the following: * Bilateral surgical oophorectomy * No spontaneous menses ≥ 1 year * No menses for \< 1 year with FSH and estradiol levels in postmenopausal range. If a study subject under the age of 60 reports prior surgery in which the ovaries were removed and if the operative report cannot be obtained to confirm bilateral salpingo-oophorectomy, the subject will have serum estradiol, LH and FSH drawn to confirm menopausal status prior to study entry * 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 * Absolute neutrophil count ≥ 1.5 x 10\^9/L * Hemoglobin ≥ 9.0 g/dL * Platelet count ≥ 70 x 10\^9/L * Creatinine ≤ 1.5 mg/dL * 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 * Any agent with estrogenic or putatively estrogenic properties, including herbal preparations, must be stopped at least one week prior to registration. * Ongoing, chronic administration of bisphosphonate therapy is allowed so long as such treatment was ongoing at the time of study entry. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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. |
| 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 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 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 |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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 for treatment of metastatic breast cancer
Anastrozole
AZD0530 | 12 |
| Phase 2 - Cohort B [Anastrozole + AZD0530] 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 | 39 |
| Phase 2 - Cohort B [Anastrozole + 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.
Anastrozole
Placebo | 20 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 8 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Phase 1 - Cohort A | Phase 2 - Cohort B [Anastrozole + AZD0530] | Phase 2 - Cohort B [Anastrozole + Placebo] | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 11 Participants | 4 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 28 Participants | 16 Participants | 55 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Asian | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Hispanic | 3 Participants | 24 Participants | 12 Participants | 39 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Non-Hispanic black or African America | 0 Participants | 4 Participants | 5 Participants | 9 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Non-Hispanic white | 9 Participants | 9 Participants | 1 Participants | 19 Participants |
| Sex: Female, Male Female | 12 Participants | 39 Participants | 20 Participants | 71 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 12 | 0 / 39 | 0 / 20 |
| other Total, other adverse events | 12 / 12 | 39 / 39 | 18 / 20 |
| serious Total, serious adverse events | 3 / 12 | 5 / 39 | 1 / 20 |
Outcome results
Primary
Phase I Cohort A: Maximum Tolerated AZD0530 Daily Dose Used in Combination With Daily Oral Anastrozole
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.
Time frame: Cycle 1: Days 1 - 28
Population: All participants enrolled to phase 1.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 - Cohort A | Phase I Cohort A: Maximum Tolerated AZD0530 Daily Dose Used in Combination With Daily Oral Anastrozole | anastrozole | 1 mg/day oral dose |
| Phase 1 - Cohort A | Phase I Cohort A: Maximum Tolerated AZD0530 Daily Dose Used in Combination With Daily Oral Anastrozole | saracatinib | 175 mg/day oral dose |
Primary
Phase II - Cohort B: Compare Treatment Groups (AZD0530 + Anastrozole Versus Anastrozole With Placebo) With Respect to Clinical Response
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
Time frame: Baseline, cycle 6
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 - Cohort A | Phase II - Cohort B: Compare Treatment Groups (AZD0530 + Anastrozole Versus Anastrozole With Placebo) With Respect to Clinical Response | Max clinical diameter % change | -61.5 percentage of tumor volume change | Standard Deviation 22.5 |
| Phase 1 - Cohort A | Phase II - Cohort B: Compare Treatment Groups (AZD0530 + Anastrozole Versus Anastrozole With Placebo) With Respect to Clinical Response | Clinical tumor volume% change | -87.9 percentage of tumor volume change | Standard Deviation 22.6 |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Compare Treatment Groups (AZD0530 + Anastrozole Versus Anastrozole With Placebo) With Respect to Clinical Response | Max clinical diameter % change | -62.3 percentage of tumor volume change | Standard Deviation 25 |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Compare Treatment Groups (AZD0530 + Anastrozole Versus Anastrozole With Placebo) With Respect to Clinical Response | Clinical tumor volume% change | -90.7 percentage of tumor volume change | Standard Deviation 11.8 |
Secondary
Phase 1-Cohort A: Peak Concentration of Each Study Drug ( AZD0530 (Saracatinib) and Anastrozole)
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
Time frame: 0 hrs, 6 hrs, 12 hrs, 24hrs, 48 hrs, 72 hrs, 7 days, 14 days, 21 days after first dose of AZD0530
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 - Cohort A | Phase 1-Cohort A: Peak Concentration of Each Study Drug ( AZD0530 (Saracatinib) and Anastrozole) | AZD0530 (saracatinib) ng/ml | 271.97 ng/ml | Standard Deviation 144.07 |
| Phase 1 - Cohort A | Phase 1-Cohort A: Peak Concentration of Each Study Drug ( AZD0530 (Saracatinib) and Anastrozole) | anastrozole ng/ml | 47.33 ng/ml | Standard Deviation 25.15 |
Secondary
Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole
Summarized as mean plasma concentrations (ng/ml) of each drug (AZD0530 (saracatinib) and Anastrozole) after exposure to dual therapy.
Time frame: 0 hrs, 6 hrs, 12 hrs, 24hrs, 48 hrs, 72 hrs, 8 days, 15 days, 22 days after first dose of AZD0530
Population: Day 21 - 1 missing sample.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 - Cohort A | Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole | AZD0530 - Cycle 1: 0 hrs | 0 ng/ml | Standard Deviation 0 |
| Phase 1 - Cohort A | Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole | AZD0530 - Cycle 1: 6 hrs | 127.47 ng/ml | Standard Deviation 57.12 |
| Phase 1 - Cohort A | Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole | AZD0530 - Cycle 1: 12 hrs | 79.1 ng/ml | Standard Deviation 33.42 |
| Phase 1 - Cohort A | Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole | AZD0530 - Cycle 1: 24 hrs | 46.17 ng/ml | Standard Deviation 24.86 |
| Phase 1 - Cohort A | Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole | AZD0530 - Cycle 1: 48 hrs | 91.33 ng/ml | Standard Deviation 39.6 |
| Phase 1 - Cohort A | Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole | AZD0530 - Cycle 1: 72 hrs | 125.49 ng/ml | Standard Deviation 52.63 |
| Phase 1 - Cohort A | Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole | AZD0530 - Day 8 | 232.23 ng/ml | Standard Deviation 91.54 |
| Phase 1 - Cohort A | Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole | AZD0530 - Day 15 | 213.52 ng/ml | Standard Deviation 84.13 |
| Phase 1 - Cohort A | Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole | AZD0530 - Day 22 | 271.97 ng/ml | Standard Deviation 144.07 |
| Phase 1 - Cohort A | Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole | Anastrozole - Day 1: 0 hrs | 26.35 ng/ml | Standard Deviation 11.55 |
| Phase 1 - Cohort A | Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole | Anastrozole - Day 1: 6 hrs | 38.2 ng/ml | Standard Deviation 26.88 |
| Phase 1 - Cohort A | Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole | Anastrozole - Day 1: 12 hrs | 33.45 ng/ml | Standard Deviation 22.13 |
| Phase 1 - Cohort A | Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole | Anastrozole - (24 hrs) | 29.33 ng/ml | Standard Deviation 21.49 |
| Phase 1 - Cohort A | Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole | Anastrozole - (48 hrs) | 32.81 ng/ml | Standard Deviation 25.15 |
| Phase 1 - Cohort A | Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole | Anastrozole - (72 hrs) | 34.08 ng/ml | Standard Deviation 20.01 |
| Phase 1 - Cohort A | Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole | Anastrozole - Day 8 | 51.00 ng/ml | Standard Deviation 22.69 |
| Phase 1 - Cohort A | Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole | Anastrozole - Day 15 | 46.75 ng/ml | Standard Deviation 28.07 |
| Phase 1 - Cohort A | Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole | Anastrozole - Day 22 | 47.33 ng/ml | Standard Deviation 25.15 |
Secondary
Phase II Cohort B: Change in Tumor Size by Comparison of Serial MRI
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.
Time frame: Baseline to 10 weeks;and baseline to 6 months
Population: 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 .
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 - Cohort A | Phase II Cohort B: Change in Tumor Size by Comparison of Serial MRI | MRI RECIST % change 10 weeks | -26.9 percentage of tumor volume change | Standard Deviation 30.4 |
| Phase 1 - Cohort A | Phase II Cohort B: Change in Tumor Size by Comparison of Serial MRI | MRI tumor volume % change 10 weeks | -46.4 percentage of tumor volume change | Standard Deviation 43.1 |
| Phase 1 - Cohort A | Phase II Cohort B: Change in Tumor Size by Comparison of Serial MRI | MRI RECIST % change 6 months | -44.6 percentage of tumor volume change | Standard Deviation 34.1 |
| Phase 1 - Cohort A | Phase II Cohort B: Change in Tumor Size by Comparison of Serial MRI | MRI tumor volume % change 6 months | -70.7 percentage of tumor volume change | Standard Deviation 29.5 |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II Cohort B: Change in Tumor Size by Comparison of Serial MRI | MRI tumor volume % change 6 months | -43.2 percentage of tumor volume change | Standard Deviation 50.9 |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II Cohort B: Change in Tumor Size by Comparison of Serial MRI | MRI RECIST % change 10 weeks | -15.9 percentage of tumor volume change | Standard Deviation 19.6 |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II Cohort B: Change in Tumor Size by Comparison of Serial MRI | MRI RECIST % change 6 months | -22.5 percentage of tumor volume change | Standard Deviation 27.1 |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II Cohort B: Change in Tumor Size by Comparison of Serial MRI | MRI tumor volume % change 10 weeks | -35.0 percentage of tumor volume change | Standard Deviation 31.7 |
Secondary
Phase II - Cohort B: Number of Participants With Pathologic Complete Response (pCR)
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.
Time frame: At completion of 4-6 cycles of therapy or after disease progression
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 - Cohort A | Phase II - Cohort B: Number of Participants With Pathologic Complete Response (pCR) | 0 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Number of Participants With Pathologic Complete Response (pCR) | 0 Participants |
Secondary
Phase II - Cohort B: The Number of Participants Achieving Clinical Benefit Defined as Complete Response (CR), or Partial Response (PR) or Stable Disease (SD)
Based on physician measurement of tumor size and by MRI measurements of tumor volume using RECIST criteria
Time frame: At the end of neoadjuvant therapy
Population: 8 patients were removed from the study due to adverse events
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1 - Cohort A | Phase II - Cohort B: The Number of Participants Achieving Clinical Benefit Defined as Complete Response (CR), or Partial Response (PR) or Stable Disease (SD) | Complete Response | 0 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: The Number of Participants Achieving Clinical Benefit Defined as Complete Response (CR), or Partial Response (PR) or Stable Disease (SD) | Partial Response | 16 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: The Number of Participants Achieving Clinical Benefit Defined as Complete Response (CR), or Partial Response (PR) or Stable Disease (SD) | Stable Disease | 0 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: The Number of Participants Achieving Clinical Benefit Defined as Complete Response (CR), or Partial Response (PR) or Stable Disease (SD) | Disease Progression | 7 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: The Number of Participants Achieving Clinical Benefit Defined as Complete Response (CR), or Partial Response (PR) or Stable Disease (SD) | Disease Progression | 2 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: The Number of Participants Achieving Clinical Benefit Defined as Complete Response (CR), or Partial Response (PR) or Stable Disease (SD) | Complete Response | 0 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: The Number of Participants Achieving Clinical Benefit Defined as Complete Response (CR), or Partial Response (PR) or Stable Disease (SD) | Stable Disease | 0 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: The Number of Participants Achieving Clinical Benefit Defined as Complete Response (CR), or Partial Response (PR) or Stable Disease (SD) | Partial Response | 17 Participants |
Secondary
Phase II - Cohort B: To Report the Pharmacokinetics (Mean Blood Levels of Drug) of AZD0530 (Saracatinib) and Anastrozole
Blood draws at protocol-specified timepoints to determine mean blood levels of drug for each of AZD0530 and Anastrozole.
Time frame: Day 28, 56, 84
Population: PK assays of AZD0530 could not be completed for all participants due to technical problems with the assay protocol
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 - Cohort A | Phase II - Cohort B: To Report the Pharmacokinetics (Mean Blood Levels of Drug) of AZD0530 (Saracatinib) and Anastrozole | AZD0530 - Day 84 | 258.6 ng/ml | Standard Deviation 100.9 |
| Phase 1 - Cohort A | Phase II - Cohort B: To Report the Pharmacokinetics (Mean Blood Levels of Drug) of AZD0530 (Saracatinib) and Anastrozole | AZD0530 - Day 28 | 264.6 ng/ml | Standard Deviation 96.8 |
| Phase 1 - Cohort A | Phase II - Cohort B: To Report the Pharmacokinetics (Mean Blood Levels of Drug) of AZD0530 (Saracatinib) and Anastrozole | AZD0530 - Day 56 | 286.4 ng/ml | Standard Deviation 65.9 |
| Phase 1 - Cohort A | Phase II - Cohort B: To Report the Pharmacokinetics (Mean Blood Levels of Drug) of AZD0530 (Saracatinib) and Anastrozole | Anastrozole - Day 28 | 52.7 ng/ml | Standard Deviation 22.3 |
| Phase 1 - Cohort A | Phase II - Cohort B: To Report the Pharmacokinetics (Mean Blood Levels of Drug) of AZD0530 (Saracatinib) and Anastrozole | Anastrozole - Day 56 | 49.9 ng/ml | Standard Deviation 21 |
| Phase 1 - Cohort A | Phase II - Cohort B: To Report the Pharmacokinetics (Mean Blood Levels of Drug) of AZD0530 (Saracatinib) and Anastrozole | Anastrozole - Day 84 | 48.3 ng/ml | Standard Deviation 17.2 |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: To Report the Pharmacokinetics (Mean Blood Levels of Drug) of AZD0530 (Saracatinib) and Anastrozole | Anastrozole - Day 28 | 37.4 ng/ml | Standard Deviation 10.4 |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: To Report the Pharmacokinetics (Mean Blood Levels of Drug) of AZD0530 (Saracatinib) and Anastrozole | Anastrozole - Day 84 | 39.5 ng/ml | Standard Deviation 11.7 |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: To Report the Pharmacokinetics (Mean Blood Levels of Drug) of AZD0530 (Saracatinib) and Anastrozole | Anastrozole - Day 56 | 37.6 ng/ml | Standard Deviation 12.3 |
Secondary
Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo
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
Time frame: From day 1 of treatment until a maximum of 6 months of treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1 - Cohort A | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Diarrhea | 23 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Rash | 24 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Alanine aminotransferase increased | 19 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Thrombocytopenia | 3 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Alkaline phosphatase increased | 11 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Alopecia | 17 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Aspartate aminotransferase increased | 20 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Neutropenia | 4 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Creatinine increased | 3 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Hot Flashes | 18 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Hyperbilirubinemia | 3 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Fatigue | 10 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Flu-like syndrome | 9 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Anorexia | 8 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Upper Respiratory Infection | 14 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Urinary Tract Infection | 13 Participants |
| Phase 1 - Cohort A | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Anemia | 7 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Urinary Tract Infection | 1 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Anemia | 1 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Neutropenia | 1 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Thrombocytopenia | 0 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Fatigue | 3 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Rash | 3 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Alopecia | 2 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Hot Flashes | 7 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Anorexia | 1 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Diarrhea | 6 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Alanine aminotransferase increased | 3 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Alkaline phosphatase increased | 0 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Aspartate aminotransferase increased | 1 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Creatinine increased | 1 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Hyperbilirubinemia | 0 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Flu-like syndrome | 1 Participants |
| Phase 2 - Cohort B [Anastrozole + Placebo] | Phase II - Cohort B: Treatment Emergent Adverse Events Associated With AZD0530 (Saracatinib) Given With Anastrozole and of Anastrozole Given With Placebo | Upper Respiratory Infection | 2 Participants |