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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2016 by University of Miami
Sponsor:
Collaborator:
Stanford University
Information provided by (Responsible Party):
Joyce Marie Slingerland, University of Miami
ClinicalTrials.gov Identifier:
NCT01216176
First received: October 5, 2010
Last updated: August 18, 2016
Last verified: August 2016
  Purpose
The investigators propose to conduct a Phase I/randomized Phase II study design in order to test the tolerability and efficacy of AZD0530 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. The Phase II cohort will permit extended assays of tolerability, initial estimates of efficacy, and the investigation of molecular predictors of drug efficacy.

Condition Intervention Phase
Breast Cancer
Drug: Anastrozole
Drug: AZD0530
Drug: Placebo
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by University of Miami:

Primary Outcome Measures:
  • Phase I Cohort A: To determine if a well tolerated dose of AZD0530 can be used in combination with anastrozole for postmenopausal women with ER+/PR+ metastatic breast cancer [ Time Frame: Cycle 1: Days 1 - 28 ] [ Designated as safety issue: Yes ]
  • Phase II - Cohort B: Compare treatment groups (AZD0530 + Anastrozole versus Anastrozole with placebo) with respect to clinical response [ Time Frame: At the end of each 28 day cycle, for a total of 6 cycles ] [ Designated as safety issue: No ]
    Clinical response is defined as percentage change/reduction in tumor size calculated from bi-dimensional clinical tumor measurement at diagnosis and on completion of neoadjuvant treatment.


Secondary Outcome Measures:
  • Phase I - Cohort A: To test the effects of giving AZD0530 and Anastrozole together on pharmacokinetics of both drugs [ Time Frame: Cycle 1: 0 hrs, 6 hrs, 12 hrs, 24hrs, 48 hrs, 72 hrs, 7 days, 14 days, 21 days after first dose of AZD0530 ] [ Designated as safety issue: No ]
    Blood draws at protocol-specified timepoints to determine pharmacokinetics of AZD0530 and Anastrozole.

  • Phase II - Cohort B: Evaluation of pathologic complete response (pCR) [ Time Frame: At the end of neoadjuvant therapy and after definitive surgery ] [ Designated as safety issue: No ]
    Evaluation of tumor specimen in patients undergoing mastectomy or breast-conserving procedure to determine response (pCR)

  • Phase II - Cohort B: Clinical Benefit (complete (CR), or partial (PR) responses or stable disease (SD)) [ Time Frame: At the end of neoadjuvant therapy ] [ Designated as safety issue: No ]
    Based on physician measurement of tumor size and by MRI measurements of tumor volume at diagnosis and prior to surgery.

  • Phase II - Cohort B: Qualitative and Quantitative Toxicities [ Time Frame: Baseline, 6 treatment cycles and up to 4-6 weeks after surgery or after therapy/withdrawal or until resolution of any toxicity ] [ Designated as safety issue: Yes ]
    Patients who have tumor removal breast surgery after neoadjuvant therapy will be assessed up to 2 months after surgery. In the event the tumor is not-operable, toxicity will evaluated by patient interview and examination for the last time 4-6 weeks after discontinuing therapy or when toxicity is resolved.

  • Phase II - Cohort B: To identify molecular/biologic correlates as indicators of treatment response [ Time Frame: At the end of neoadjuvant therapy and after definitive surgery ] [ Designated as safety issue: No ]
    Evaluation of biomarkers including Ki67 and p27, EGFR, Her2, Src, Akt and MAPK Levels, localization and phosphorylation as assayed by immunohistochemistry. Other biomarkers may be considered pending initial IHC results.

  • Phase II cohort B: Evaluation of clinical response defined as percentage change/reduction in tumor size by comparison of serial MRI [ Time Frame: Baseline , 10 weeks from study start date and pre-operative ] [ Designated as safety issue: No ]
    MRI will be used to compare tumor size prior to drug therapy , at 10 weeks after start of treatment and prior to surgery after completion of study medication


Estimated Enrollment: 72
Study Start Date: October 2008
Estimated Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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
Drug: Anastrozole Drug: AZD0530
Active Comparator: 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 6 months treatment completed.
Drug: Anastrozole Drug: AZD0530
Placebo Comparator: 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 or 6 months treatment completed.
Drug: Anastrozole Drug: Placebo

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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
  • 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
  • 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.

Exclusion Criteria - Phase 2 (Cohort B):

  • Prior chemotherapy, endocrine therapy or radiotherapy for the presenting breast cancer. Prior incidence and treatment of contralateral invasive or non-invasive breast cancer is not an exclusion criterion.
  • Inflammatory breast cancer, clinically defined as the presence of erythema or induration involving one-third or more of the breast, or pathologically defined as dermal lymphatic invasion
  • Prior excisional biopsy or complete resection of the primary invasive tumor (prior sentinel node biopsy allowed)
  • Prior ipsilateral radiation therapy for invasive or non-invasive breast cancer
  • Distant metastasis is an exclusion criterion - Isolated ipsilateral supraclavicular node involvement and/or direct invasion of the primary tumor into skin is allowed
  • 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
  • Current therapy with hormone replacement therapy, or any hormonal agent such as raloxifene, tamoxifen, or other selective estrogen receptor modulators (agents must be stopped for one week prior to randomization)
  • Presence of neuropathy ≥ grade 2 (NCI-CTC AE 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. 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.
  • AZD0530 is a substrate and inhibitor of CYP3A4. Since concurrent administration of AZD0530 with other CYP3A4 substrates has been shown to be well tolerated, continuation or initiation of medically indicated drugs that are substrates of CYP3A4 is permitted at MD discretion. Drugs listed in Appendix XI that are known to strongly induce or inhibit CYP3A4 activity should be discontinued prior to study entry and should not be initiated during protocol treatment.
  • Any evidence of severe or uncontrolled systemic psychiatric or medical conditions (eg. 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 prior to study entry and/or symptomatic pulmonary (pleural or parenchymal) disease.
  • Subjects unwilling or unable to undergo breast MRI as required by protocol will be excluded from study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01216176

Contacts
Contact: University of Miami Sylvester Comprehensive Cancer Center 866-574-5124 sylvester@emergingmed.com

Locations
United States, California
Stanford University Terminated
Palo Alto, California, United States, 94304
United States, Florida
University of Miami Sylvester Comprehensive Cancer Center Recruiting
Miami, Florida, United States, 33136
Contact: University of Miami Sylvester Comprehensive Cancer Center    866-574-5124    sylvester@emergingmed.com   
Principal Investigator: Joyce Slingerland, MD         
Sponsors and Collaborators
Joyce Marie Slingerland
Stanford University
Investigators
Principal Investigator: Joyce Slingerland, MD University of Miami Sylvester Comprehensive Cancer Center
  More Information

Responsible Party: Joyce Marie Slingerland, Professor, University of Miami
ClinicalTrials.gov Identifier: NCT01216176     History of Changes
Other Study ID Numbers: 20080325  SCCC-2008002 
Study First Received: October 5, 2010
Last Updated: August 18, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Miami:
Breast Cancer
Phase II for newly diagnosed breast cancer
Postmenopausal
Metastatic Phase I ONLY
AZD0530
Anastrozole
Phase I for metastatic disease
Pharmacokinetic
PK
Hormone Receptor
Estrogen Receptor
Progesterone Receptor
ER+
PR+
HER negative
Aromatase Inhibitors

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Hormones
Anastrozole
Saracatinib
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists

ClinicalTrials.gov processed this record on September 30, 2016