Clinical Trials /

PD 0332991 and Anastrozole for Stage 2 or 3 Estrogen Receptor Positive and HER2 Negative Breast Cancer

NCT01723774

Description:

A Phase II study to investigate the potential utility of PD 0332991 in the treatment of early stage ER+ Human epidermal growth factor receptor 2 (HER2)- breast cancer, to investigate whether the combination of PD 0332991 and anastrozole is able to: 1) improve the pathologic complete response rate when compared to the historical control of single agent aromatase inhibitors, 2) result in fewer patients with on therapy Ki67>10% compared to historical control.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">PD 0332991</span> and <span class="go-doc-concept go-doc-intervention">Anastrozole</span> for Stage 2 or 3 Estrogen Receptor Positive and <span class="go-doc-concept go-doc-biomarker">HER2</span> Negative Breast Cancer

Title

  • Brief Title: PD 0332991 and Anastrozole for Stage 2 or 3 Estrogen Receptor Positive and HER2 Negative Breast Cancer
  • Official Title: A Phase II Trial of Neoadjuvant PD 0332991, a Cyclin-Dependent Kinase (Cdk) 4/6 Inhibitor, in Combination With Anastrozole in Women With Clinical Stage 2 or 3 Estrogen Receptor Positive and HER2 Negative Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT01723774

    ORG ID: 201301106

    Trial Conditions

    Breast Neoplasms

    Trial Interventions

    Drug Synonyms Arms
    PD0332991 Arm 1: PIK3CA Wild Type Cohort, Arm 2: PIK3CA Mutant Type Cohort, Arm 3: Endocrine Resistant Cohort
    Anastrozole Arimidex Arm 1: PIK3CA Wild Type Cohort, Arm 2: PIK3CA Mutant Type Cohort, Arm 3: Endocrine Resistant Cohort
    Goserelin Zoladex, Decapeptide I Arm 1: PIK3CA Wild Type Cohort, Arm 2: PIK3CA Mutant Type Cohort, Arm 3: Endocrine Resistant Cohort

    Trial Purpose

    A Phase II study to investigate the potential utility of PD 0332991 in the treatment of
    early stage ER+ Human epidermal growth factor receptor 2 (HER2)- breast cancer, to
    investigate whether the combination of PD 0332991 and anastrozole is able to: 1) improve the
    pathologic complete response rate when compared to the historical control of single agent
    aromatase inhibitors, 2) result in fewer patients with on therapy Ki67>10% compared to
    historical control.

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    Arm 1: PIK3CA Wild Type Cohort Experimental Tumor biopsy for testing/research at baseline and Cycle 1 Day 15 Cycle 0 is 28 days of anastrozole PO daily and, if premenopausal, goserelin SC every 28 days. Cycles 1-5: PD 0332991 combined with anastrozole (and goserelin if premenopausal) is to be (4) 28-day cycles followed by a 5th cycle of 10-12 days duration consisting of daily PD 0332991 and anastrozole (last dose day before surgery) Standard surgery will be performed per institutional standards 2-4 weeks following the completion of Cycle 4 in those who did not receive Cycle 5. In patients who receive Cycle 5, surgery occurs on Day 11, 12, or 13 of Cycle 5. Patients who derived benefit from the therapy have the option of taking PD 0332991 in combination with anastrozole for 23 cycles after surgery and adjuvant chemotherapy and radiation if indicated. It should be re-started at least 4 weeks after the completion of chemotherapy and radiation therapy if these treatments were planned. PD0332991, Anastrozole, Goserelin
    Arm 2: PIK3CA Mutant Type Cohort Experimental Tumor biopsy for testing/research at baseline and Cycle 1 Day 15 Cycle 0 is 28 days of anastrozole PO daily and, if premenopausal, goserelin SC every 28 days. Cycles 1-5: PD 0332991 combined with anastrozole (and goserelin if premenopausal) is to be (4) 28-day cycles followed by a 5th cycle of 10-12 days duration consisting of daily PD 0332991 and anastrozole (last dose day before surgery) Standard surgery will be performed per institutional standards 2-4 weeks following the completion of Cycle 4 in those who did not receive Cycle 5. In patients who receive Cycle 5, surgery occurs on Day 11, 12, or 13 of Cycle 5. Patients who derived benefit from the therapy have the option of taking PD 0332991 in combination with anastrozole for 23 cycles after surgery and adjuvant chemotherapy and radiation if indicated. It should be re-started at least 4 weeks after the completion of chemotherapy and radiation therapy if these treatments were planned. PD0332991, Anastrozole, Goserelin
    Arm 3: Endocrine Resistant Cohort Experimental Tumor biopsy for testing/research at baseline and Cycle 1 Day 15 Cycles 1-5: PD 0332991 combined with anastrozole (and goserelin if premenopausal) is to be (4) 28-day cycles followed by a 5th cycle of 10-12 days duration consisting of daily PD 0332991 and anastrozole (last dose day before surgery) Standard surgery will be performed per institutional standards 2-4 weeks following the completion of Cycle 4 in those who did not receive Cycle 5. In patients who receive Cycle 5, surgery occurs on Day 11, 12, or 13 of Cycle 5. Patients who derived benefit from the therapy have the option of taking PD 0332991 in combination with anastrozole for 23 cycles after surgery and adjuvant chemotherapy and radiation if indicated. It should be re-started at least 4 weeks after the completion of chemotherapy and radiation therapy if these treatments were planned. PD0332991, Anastrozole, Goserelin

    Eligibility Criteria

    Pre-registration PIK3CA Mutant Inclusion

    - Clinical T2-T4c, any N, M0 invasive ER+ (Allred Score of 6-8) and HER2 negative (0 or
    1+ by IHC or FISH negative for amplification) breast cancer, by AJCC 7th edition
    clinical staging, with the goal being surgery to completely excise the tumor in the
    breast and the lymph node. Note: Patients with invasive ER+ (Allred Score of 6-8)
    HER2- breast cancer or DCIS in the contralateral breast the patient are eligible

    - Female 18 years of age

    - ECOG performance status of 0, 1 or 2

    - Life expectancy > 4 months

    - Premenopausal, patient must be willing to comply with pregnancy requirements

    - Adequate organ and marrow function

    - leukocytes 3,000/mcL

    - absolute neutrophil count 1,500/mcL

    - platelets 100,000/mcL

    - total bilirubin ULN

    - AST(SGOT)/ and ALT(SGPT) < 2.5 X ULN

    - Creatinine ULN

    - Able to understand and willing to sign an IRB-approved written informed consent
    document

    Exclusion

    - Prior treatment of this cancer including: surgery, radiation, chemotherapy,
    biotherapy, hormonal therapy, investigational agent prior to study entry

    - Receiving any investigational agents

    - Prior therapy with any Cdk4 inhibitor

    - Any of the following in the previous 6 months: myocardial infarction, severe/unstable
    angina, coronary/peripheral artery bypass graft, symptomatic congestive heart
    failure, cerebrovascular accident, transient ischemic attack, symptomatic pulmonary
    embolism

    - Uncontrolled intercurrent illness including, but not limited to: ongoing or active
    infection, symptomatic congestive heart failure, unstable angina pectoris,
    uncontrolled symptomatic cardiac arrhythmia, psychiatric illness/social situations
    that would limit compliance with study requirements

    - Pregnant/nursing

    - Unwilling to employ adequate contraception

    - Known HIV-positive on combination antiretroviral therapy

    - Evidence of inflammatory cancer

    - Known metastatic disease

    - Current use of anticoagulation therapy

    - Previous excisional biopsy of the breast cancer or sentinel lymph node biopsy

    - Any condition that impairs patient's ability to swallow PD 0332991 tablets (e.g.,
    gastrointestinal tract disease resulting in an inability to take oral medication or a
    requirement for IV alimentation, prior surgical procedures affecting absorption)

    - History of allergic reactions attributed to compounds of similar chemical or biologic
    composition to PD 0332991 or other agents used in the study

    - Corrected QT interval >470 msec

    Registration PIK3CA Mutant Inclusion The criteria below must be met in addition to the
    pre-registration criteria, except treatment with endocrine therapy for this cancer is
    allowed prior to registration

    - PIK3CA mutant cohort: tumor PIK3CA mutation present

    - Premenopausal women, serum estradiol level in postmenopausal range 7 days prior to
    registration

    Exclusion Criteria below must be met in addition to the pre-registration criteria

    - Receiving medications (within the last 7 days prior to registration) that have the
    potential of prolonging the QT interval

    - Current use or anticipated need for food or drugs that are known strong CYP3A4
    inhibitors (i.e. grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole,
    posaconazole, erythromycin, clarithromycin, telithromycin, indinavir, saquinavir,
    ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, nefazodone,
    diltiazem, and delavirdine) or inducers (i.e. dexamethasone, glucocorticoids,
    progesterone, rifampin, phenobarbital, St. John's wort)

    - Receiving medications that are proton pump inhibitors

    PIK3CA Wild Type Inclusion

    - Clinical T2-T4c, any N, M0 invasive ER+ (Allred Score of 6-8) and HER2 negative (0 or
    1+ by IHC or FISH negative for amplification) breast cancer, by AJCC 7th edition
    clinical staging, with the goal being surgery to completely excise the tumor in the
    breast and the lymph node. Note: Patients with invasive ER+ (Allred Score of 6-8)
    HER2- breast cancer or DCIS in the contralateral breast the patient are eligible

    - For the PIK3CA wild type cohort: tumor PIK3CA mutation absent. Note that if a patient
    did not have sufficient research tissue for PIK3CA sequencing at pre-registration or
    if PIK3CA sequencing result is delayed, she could be registered and enrolled on the
    PD991 trial without assigning to a particular cohort at the time of enrollment.
    PIK3CA sequencing will be performed in the future on tumors collected at subsequent
    time points to assign the treatment cohort or when the PIK3CA sequencing data is
    available

    - For the endocrine resistant cohort: Ki67 > 10% by central testing at Washington
    University AMP laboratory from a tumor biopsy performed after at least 2 weeks on
    neoadjuvant endocrine therapy. Note that prior neoadjuvant endocrine therapy could
    include any endocrine therapy (including aromatase inhibitor, tamoxifen, fulvestrant)
    alone or in combination, or endocrine therapy in combination with any investigational
    agent that is not a Cdk 4/6 inhibitor

    *Patients who had a Day 17 Ki67 > 10% from the NCI9170 trial are eligible for the
    endocrine resistant cohort

    - Female >18 years of age

    - ECOG performance status of 0, 1 or 2

    - Life expectancy > 4 months

    - If premenopausal, patient must be willing to comply with pregnancy requirements

    - Adequate organ and marrow function:

    - leukocytes 3,000/mcL

    - absolute neutrophil count 1,500/mcL

    - platelets 100,000/mcL

    - total bilirubin ULN

    - AST(SGOT)/ and ALT(SGPT) < 2.5 X ULN

    - Creatinine ULN

    - In premenopausal women, serum estradiol level in postmenopausal range 7 days prior
    to registration.

    - Able to understand and willing to sign an IRB-approved written informed consent
    document

    Exclusion

    - Prior treatment of this cancer including: Surgery, Radiation therapy, Chemotherapy,
    Biotherapy, Hormonal therapy, Investigational agent prior to study entry

    - Receiving any other investigational agents

    - Prior therapy with any Cdk4 inhibitor

    - Any of the following in the previous 6 months: myocardial infarction, severe/unstable
    angina, coronary/peripheral artery bypass graft, symptomatic congestive heart
    failure, cerebrovascular accident, transient ischemic attack, symptomatic pulmonary
    embolism

    - Uncontrolled intercurrent illness including, but not limited to: ongoing or active
    infection, symptomatic congestive heart failure, unstable angina pectoris,
    uncontrolled symptomatic cardiac arrhythmia, psychiatric illness/social situations
    that would limit compliance with study requirements

    - Pregnant/nursing

    - Unwilling to employ adequate contraception

    - Known HIV-positive on combination antiretroviral therapy

    - Evidence of inflammatory cancer

    - Known metastatic disease

    - Current use of anticoagulation therapy

    - Previous excisional biopsy of the breast cancer or sentinel lymph node biopsy

    - Any condition that impairs patient's ability to swallow PD 0332991 tablets (e.g.,
    gastrointestinal tract disease resulting in an inability to take oral medication or a
    requirement for IV alimentation, prior surgical procedures affecting absorption)

    - History of allergic reactions attributed to compounds of similar chemical or biologic
    composition to PD 0332991 or other agents used in the study

    - Corrected QT interval >470 msec

    - Receiving medications (within the last 7 days prior to registration) that have the
    potential of prolonging the QT interval.

    - Current use or anticipated need for food or drugs that are known strong CYP3A4
    inhibitors (i.e. grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole,
    posaconazole, erythromycin, clarithromycin, telithromycin, indinavir, saquinavir,
    ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, nefazodone,
    diltiazem, and delavirdine) or inducers (i.e. dexamethasone, glucocorticoids,
    progesterone, rifampin, phenobarbital, St. John's wort)

    - Receiving medications that are proton pump inhibitors

    Endocrine Resistant Inclusion

    - Clinical T2-T4c at diagnosis or screening, any N, M0 invasive ER+ (Allred Score at
    least 3 or > 1% ER positivity) and HER2 negative (0 or 1+ by IHC or FISH negative or
    equivocal) breast cancer, by AJCC 7th edition clinical staging, with the goal being
    surgery to completely excise the tumor in the breast and the lymph node. Note:
    Patients with invasive breast cancer that is ER pos, HER2 neg or equivocal or DCIS in
    the contralateral breast are eligible; multi-focal diseases are not excluded. The
    dominant lesion will be followed per protocol

    - Ki67 > 10% by central testing at Washington University AMP laboratory from a tumor
    biopsy performed after at least 2 weeks on neoadjuvant endocrine therapy. If Ki67 is
    > 10% by local testing, the Ki67 slide and H&E slide need to be reviewed by the study
    pathologist to confirm eligibility (discuss with Study Chair). For patients external
    to Washington University, please contact the Washington University coordinator by
    email so that a screening ID# can be assigned prior to shipment of the slides

    - Female 18 years of age

    - ECOG performance status of 0, 1 or 2

    - Pre- or post-menopausal women are eligible. If premenopausal, patient must be willing
    to comply with pregnancy requirements and agrees with GnRH agonist therapy for
    ovarian suppression during the study

    - Adequate organ and marrow function:

    - Leukocytes 3,000/mcL

    - Absolute neutrophil count 1,500/mcL

    - Platelets 100,000/mcL

    - Total bilirubin ULN

    - AST(SGOT)/ and ALT(SGPT) < 2.5 X ULN

    - Creatinine ULN

    - Able to understand and willing to sign an IRB-approved written informed consent
    document

    Exclusion

    - Prior treatment of this cancer including: Surgery, Radiation, Chemotherapy

    - Receiving any other investigational agents

    - Prior therapy with Cdk4 inhibitor

    - Any of the following in the previous 6 months: myocardial infarction, severe/unstable
    angina, coronary/peripheral artery bypass graft, symptomatic congestive heart
    failure, cerebrovascular accident, transient ischemic attack, symptomatic pulmonary
    embolism

    - Uncontrolled intercurrent illness including, but not limited to: ongoing or active
    infection, symptomatic congestive heart failure, unstable angina pectoris,
    uncontrolled symptomatic cardiac arrhythmia, psychiatric illness/social situations
    that would limit compliance with study requirements

    - Pregnant/nursing

    - Unwilling to employ adequate contraception

    - Known HIV-positive on combination antiretroviral therapy

    - Known metastatic disease

    - Current use of anticoagulation therapy

    - Previous excisional biopsy of the breast cancer or sentinel lymph node biopsy

    - Any condition that impairs patient's ability to swallow PD 0332991 tablets (e.g.,
    gastrointestinal tract disease resulting in an inability to take oral medication or a
    requirement for IV alimentation, prior surgical procedures affecting absorption)

    - History of allergic reactions attributed to compounds of similar chemical or biologic
    composition to PD 0332991 or other agents used in the study

    - Corrected QT interval >470 msec

    - Receiving medications (within the last 7 days prior to registration) that have the
    potential of prolonging the QT interval

    - Current use or anticipated need for food or drugs that are known strong CYP3A4
    inhibitors (i.e. grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole,
    posaconazole, erythromycin, clarithromycin, telithromycin, indinavir, saquinavir,
    ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, nefazodone,
    diltiazem, and delavirdine) or inducers (i.e. dexamethasone, glucocorticoids,
    progesterone, rifampin, phenobarbital, St. John's wort)

    Adjuvant Inclusion

    - Derived benefit from PD 0332991 in the neoadjuvant setting in this trial. This
    includes the 26 patients who achieved complete cell cycle arrest only after the
    addition of PD 0332991 (C1D1 Ki67 >2.7% and C1D15 Ki67 2.7%) from the main study
    (PIK3CA WT, mutant, or unknown cohorts) as well as any patients who have a Ki67 10%
    on C1D15 biopsy in the endocrine resistant cohort

    - ECOG performance status of 0, 1 or 2

    - Premenopausal, patient must be willing to comply with pregnancy requirements laid out

    - Adequate organ and marrow function

    - leukocytes 3,000/mcL

    - absolute neutrophil count 1,500/mcL

    - platelets 100,000/mcL

    - total bilirubin ULN

    - AST(SGOT)/ and ALT(SGPT) 2.5 X ULN

    - Creatinine ULN

    - Underwent surgery of the breast and axilla for curative intent

    - At least 4 weeks post completion of adjuvant chemotherapy and radiation therapy if
    indicated

    - Patients who already started on adjuvant hormonal therapy are eligible under the
    following conditions:

    - For the 26 patients who enrolled in the initial cohorts and derived benefit from
    neoadjuvant PD 0332991 (C1D1 Ki67 >2.7% and C1D15 Ki67 2.7%), adjuvant PD
    0332991 should be initiated as soon as possible if adjuvant hormonal therapy has
    been initiated and the patient has completed radiation if indicated

    - For patients who enrolled in the endocrine resistant cohort and derived benefit
    from neoadjuvant PD 0332991 (C1D15 Ki67 10%), adjuvant PD 0332991 should be
    initiated within 6 months or sooner after initation of adjuvant hormonal therapy

    - Able to understand and willing to sign an IRB-approved written informed consent
    document

    Exclusion

    - Any of the following in the previous 6 months: myocardial infarction, severe/unstable
    angina, coronary/peripheral artery bypass graft, symptomatic congestive heart
    failure, cerebrovascular accident, transient ischemic attack, symptomatic pulmonary
    embolism

    - Uncontrolled intercurrent illness including, but not limited to: ongoing or active
    infection, symptomatic congestive heart failure, unstable angina pectoris,
    uncontrolled symptomatic cardiac arrhythmia, ssychiatric illness/social situations
    that would limit compliance with study requirements

    - Pregnant/nursing

    - Unwilling to employ adequate contraception

    - Known HIV-positive on combination antiretroviral therapy. -Known metastatic disease

    - Any condition that impairs patient's ability to swallow PD 0332991 tablets (e.g.,
    gastrointestinal tract disease resulting in an inability to take oral medication or a
    requirement for IV alimentation, prior surgical procedures affecting absorption)

    - History of allergic reactions attributed to compounds of similar chemical or biologic
    composition to PD 0332991 or other agents used in the study

    - Corrected QT interval >470 msec

    - Receiving medications (within the last 7 days prior to registration) that have the
    potential of prolonging the QT interval

    - Current use or anticipated need for food or drugs that are known strong CYP3A4
    inhibitors (i.e. grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole,
    posaconazole, erythromycin, clarithromycin, telithromycin, indinavir, saquinavir,
    ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, nefazodone,
    diltiazem, and delavirdine) or inducers (i.e. dexamethasone, glucocorticoids,
    progesterone, rifampin, phenobarbital, St. John's wort)

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Female

    Primary Outcome Measures

    Complete cell cycle arrest in women without PIK3CA hotspot mutation (PIK3CA Wild Type Cohort)

    Complete cell cycle arrest in women with endocrine resistant cancer

    Secondary Outcome Measures

    Rate of PEPI 0 score

    Radiologic response rate

    Ki67 level post 2 weeks of PD 332991

    Concentration of PD 0332991

    Rate of cell cycle arrest

    Ki67 level of tumor specimens

    Pathologic complete response (pCR) rate

    Concentration of anastrozole

    Safety of PD 0332991 in combination in anastrozole as measured by frequency and grade of adverse events

    Complete cell cycle arrest in women with PIK3CA hotspot mutation

    Safety profile of study therapy during adjuvant therapy as measured by frequency and grade of adverse event

    Overall survival

    Relapse-free survival

    Clinical response rate

    Local recurrence rate

    Regional recurrence rate

    Distant recurrence rate

    Rate of second primary breast cancer

    Rate of second primary cancer (non-breast)

    Trial Keywords