Trial record 16 of 1662 for:    breast,cancer,treatment | Open Studies

A Pharmacokinetic and Randomized Trial of Neoadjuvant Treatment With Anastrozole Plus AZDO530 in Postmenopausal Patients With Hormone Receptor Positive Breast Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by University of Miami Sylvester Comprehensive Cancer Center
Sponsor:
Collaborator:
Doris Duke Charitable Foundation
Information provided by (Responsible Party):
University of Miami Sylvester Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01216176
First received: October 5, 2010
Last updated: April 7, 2014
Last verified: April 2014
  Purpose

The investigators propose to conduct a Phase I/randomized Phase II study design in order to test the tolerability and efficacy or AZD0530 when used together with anastrozole in therapy of ER+ and/or PR+ postmenopausal breast cancer. The Phase I pharmacokinetic (PK) cohort of the study (cohort A) will be conducted in postmenopausal women with metastatic disease and will ascertain safety and toxicity. Patients in the randomized Phase II cohort of the study (cohort B) will consist of postmenopausal women with locally advanced ER+ breast cancer who are 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 (protein and RNA expression profiles) and cellular assays (measures of TICs) as predictors of drug efficacy.


Condition Intervention Phase
Breast Cancer
Drug: Anastrozole
Drug: ADZ0530
Drug: Placebo
Procedure: Pharmacokinetic studies
Procedure: Definitive Surgery
Procedure: Core Biopsy
Genetic: Tumor Tissue Collection for Genetic and Molecular Studies
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
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 AZDO530 in Postmenopausal Patients With Hormone Receptor Positive Breast Cancer

Resource links provided by NLM:


Further study details as provided by University of Miami Sylvester Comprehensive Cancer Center:

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 alone 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 as measured by caliper measurement by MD and by dynamic contrast-enhanced magnetic resonance imaging (MRI) measurements of tumor volume at diagnosis and on completion of neoadjuvant treatment prior to surgery.


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 ADZ0530 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 Response (complete (CR), or partial (PR) responses) [ Time Frame: At the end of each 28 day cycle, for a total of 6 cycles ] [ Designated as safety issue: No ]
    Measured by physician measurement of tumor size and by MRI measurements of tumor volume at diagnosis and prior to surgery.

  • Phase II - Cohort B: Clinical Benefit (complete (CR), or partial (PR) responses or stable disease (SD)) [ Time Frame: At the end of each 28 day cycle, for a total of 6 cycles ] [ Designated as safety issue: No ]
    Measured by 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 2 months from end of therapy/withdrawal ] [ Designated as safety issue: Yes ]
  • Phase II - Cohort B: Progression-Free Survival [ Time Frame: 6, 12, and 18 months ] [ Designated as safety issue: No ]
  • Phase II - Cohort B: Overall Survival [ Time Frame: 6, 12, and 18 months ] [ Designated as safety issue: No ]
  • 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.


Estimated Enrollment: 78
Study Start Date: October 2008
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase 1 - Cohort A Drug: Anastrozole
1 mg orally per day
Drug: ADZ0530
175 mg orally per day or as otherwise specified in protocol
Procedure: Pharmacokinetic studies
Blood draws at protocol-specified timepoints to determine pharmacokinetics of ADZ0530 and Anastrozole.
Other Name: PK
Procedure: Core Biopsy
Core Biopsy at Baseline, snap frozen, paraffin-embedded
Active Comparator: Phase 2 - Cohort B [Anastrozole + AZ0530] Drug: Anastrozole
1 mg orally per day
Drug: ADZ0530
175 mg orally per day or as otherwise specified in protocol
Procedure: Definitive Surgery
Breast Conserving Mastectomy - after completion of neoadjuvant therapy
Procedure: Core Biopsy
Core Biopsy at Baseline, snap frozen, paraffin-embedded
Genetic: Tumor Tissue Collection for Genetic and Molecular Studies
Recovery of tumor tissue at the time of definitive surgery - snap frozen, for correlative genetic and molecular studies.
Placebo Comparator: Phase 2 - Cohort B [Anastrazole + Placebo] Drug: Anastrozole
1 mg orally per day
Drug: Placebo
175 mg orally per day or as otherwise specified in protocol
Procedure: Definitive Surgery
Breast Conserving Mastectomy - after completion of neoadjuvant therapy
Procedure: Core Biopsy
Core Biopsy at Baseline, snap frozen, paraffin-embedded
Genetic: Tumor Tissue Collection for Genetic and Molecular Studies
Recovery of tumor tissue at the time of definitive surgery - snap frozen, for correlative genetic and molecular studies.

  Eligibility

Ages Eligible for Study:   18 Years and older
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 > 1.5 x 109/L
    • Hemoglobin > 9.0 g/dL
    • Platelet count > 100 x 109/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
  • Stage II (minimum tumor size > 3 cm) or Stage III disease (except inflammatory breast cancer), as defined by the AJCC Staging Manual, 6th Edition, 2002
  • 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)
  • No prior chemotherapy, radiotherapy, or endocrine therapy for invasive or noninvasive breast cancer
  • 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 109/L
    • Hemoglobin > 9.0 g/dL
    • Platelet count > 100 x 109/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.

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
  • The presence of any other medical or psychiatric disorder that, in the opinion of the treating physician, would contraindicate the use of the drugs in this protocol or place the subject at undue risk for treatment complications
  • 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 that are known to significantly modulate CYP3A4 activity or are metabolized by CYP3A4 should be excluded from study. See Appendix XI. List of medications which inhibit, induced or utilize the CYP3A metabolic pathway
  • Any evidence of severe or uncontrolled systemic 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 Stage II or Stage III breast cancer
  • Inflammatory BC, 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
  • Bilateral or multifocal invasive breast cancer
  • Distant metastasis - Isolated ipsilateral supraclavicular node involvement 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 two weeks 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
  • The presence of any other medical or psychiatric disorder that, in the opinion of the treating physician, would contraindicate the use of the drugs in this protocol or place the subject at undue risk for treatment complications
  • 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 that are known to significantly modulate CYP3A4 activity or are metabolized by CYP3A4 should be excluded from study. See Appendix XI. List of medications which inhibit, induced, or utilize the CYP3A metabolic pathway.
  • Any evidence of severe or uncontrolled systemic 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, interstitial pulmonary infiltrates on high resolution CT scan prior to study entry and/or symptomatic pulmonary (pleural or parenchymal) disease.
  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, 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   
Sub-Investigator: Stefan Gluck, MD         
Principal Investigator: Joyce Slingerland, MD         
Sub-Investigator: Catherine Welsh, MD         
Sub-Investigator: Judith Hurley, MD         
Sub-Investigator: Stephen Richman, MD         
Sub-Investigator: Pearl Seo, MD         
Sub-Investigator: Orlando Silva, MD         
Sub-Investigator: Eli Avisar, MD         
Sub-Investigator: Dido Franceschi, MD         
Sub-Investigator: Frederick Moffat, MD         
Sub-Investigator: Steven Rodgers, MD         
Sub-Investigator: Carmen Gomez-Fernandez, MD         
Sub-Investigator: Merce Jorda, MD         
Sub-Investigator: Richard Kiszonas, MD         
Sub-Investigator: Monica Yepes, MD         
Sub-Investigator: Alberto Montero, MD         
Sub-Investigator: Eugene Ahn, MD         
Sub-Investigator: Maria Restrepo, MD         
Sub-Investigator: Julia Lee, MD         
Sponsors and Collaborators
University of Miami Sylvester Comprehensive Cancer Center
Doris Duke Charitable Foundation
Investigators
Study Chair: Joyce Slingerland, MD University of Miami Sylvester Comprehensive Cancer Center
  More Information

No publications provided

Responsible Party: University of Miami Sylvester Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01216176     History of Changes
Other Study ID Numbers: UMIAMI-20080325, SCCC-2008002
Study First Received: October 5, 2010
Last Updated: April 7, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Miami Sylvester Comprehensive Cancer Center:
Breast Cancer
Postmenopausal
Metastatic
AZD0530
Anastrozole
Phase I
Phase II
Pharmacokinetic
PK
Hormone Receptor
Estrogen Receptor
Progesterone Receptor
ER+
PR+
HER+
Aromatase Inhibitors

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

ClinicalTrials.gov processed this record on July 23, 2014