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

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 -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)

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
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)

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
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
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)