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

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

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

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.

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 endocrine therapy 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.

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 endocrine therapy 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.

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 endocrine therapy 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.

Number of Participants With Complete Cell Cycle Arrest at Cycle 1 Day 15 (PIK3CA Wild Type Cohort Only)

Number of Participants With Complete Cell Cycle Arrest at Cycle 1 Day 15 (Endocrine Resistant Cohort Only)

Number of Participants With Complete Cell Cycle Arrest at Cycle 1 Day 15 ( PIK3CA Mutant Type Cohort Only)

The clinical response rate is the number of patients whose disease meets the WHO criteria of complete or partial response prior to surgery divided by the total number of eligible patients who began combination neoadjuvant treatment. Complete Response (CR) is defined as the disappearance of all known disease based on a comparison between the pre-treatment measurements and the measurements taken at the completion of neo-adjuvant therapy (that is, at the end of cycle 4 neo-adjuvant combination therapy). In addition there is no appearance of new lesions. Partial Response (PR) is defined as a 50% or greater decrease in the product of the bidimensional measurements of the lesion (total tumor size) between the pre-treatment measurements and the measurements taken at the completion of neo-adjuvant therapy (that is, at the end of cycle 4 neo-adjuvant combination therapy). In addition there can be no appearance of new lesions or progression of any lesion.

The radiological response rate is the number of patients whose disease meets with WHO criteria for complete or partial response at the evaluation prior to surgery divided by the total number of eligible patients who began combination neo-adjuvant therapy. Complete Response (CR) is defined as the disappearance of all known disease based on a comparison between the pre-treatment measurements and the measurements taken at the completion of neo-adjuvant therapy (that is, at the end of cycle 4 neo-adjuvant combination therapy). In addition there is no appearance of new lesions. Partial Response (PR) is defined as a 50% or greater decrease in the product of the bidimensional measurements of the lesion (total tumor size) between the pre-treatment measurements and the measurements taken at the completion of neo-adjuvant therapy (that is, at the end of cycle 4 neo-adjuvant combination therapy). In addition there can be no appearance of new lesions or progression of any lesion.

Safety of PD 0332991 in Combination in Anastrozole as Measured by Frequency and Grade of Related Adverse Events

The maximum grade for each type of adverse event will be recorded for each patient using the NCI-CTCAE v4.0 coding scheme, and frequency tables will be reviewed to determine patterns. Additionally, the relationship (possibly related, probably related, and definitely related) of the adverse event(s) to the study treatment will be taken into consideration.

From start of treatment through 30 days after completion of an estimated 4 months of neoadjuvant therapy

Preoperative endocrine prognostic index (PEPI) score is derived from four factors assigned a numerical score following neoadjuvant endocrine therapy, including Ki67 expression in the surgical specimen, pathologic tumor size (indicated as "T" below), lymph node status (indicated as "N" below), and estrogen receptor (ER) level (indicated as ER Allred below). PEPI-0 score indicates T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2. It predicts a low risk of recurrence.

Cycle 1 day 15 and at time of surgery (approximately 2-4 weeks post completion of cycle 4 - each cycle is 28 days)

-A pathologic complete response is defined as no histology evidence of invasive tumor cells in the surgical breast specimen and sentinel or axillary lymph nodes.

Safety Profile of Study Therapy During Adjuvant Therapy as Measured by Frequency and Grade of Adverse Event

The maximum grade for each type of adverse event will be recorded for each patient using the NCI-CTCAE v4.0 coding scheme, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.

From start of adjuvant therapy through 30 days after completion of adjuvant therapy (estimated to be 2 years)

Local recurrence is defined as histologic evidence of ductal carcinoma in situ or invasive breast cancer in the ipsilateral breast or chest wall.

Regional recurrence is defined as the cytologic or histologic evidence of disease in the ipsilateral internal mammary, ipsilateral supraclavicular, ipsilateral infraclavicular and/or ipsilateral axillary nodes or soft tissue of the ipsilateral axilla.

Distant recurrence is defined as the cytologic, histologic, and/or radiographic evidence of disease in the skin, subcutaneous tissue, lymph nodes (other than local or regional metastasis), lung, bone narrow, central nervous system or histologic and/or radiographic evidence of skeletal or liver metastasis.

Second primary breast cancer is defined histologic evidence of ductal carcinoma in situ or invasive breast cancer in the contralateral breast or chest wall.

Second primary cancer (non-breast) is defined as any non-breast second primary cancer other than squamous or basal cell carcinoma of the skin, melanoma in situ, or carcinoma in situ of the cervix is to be reported and should be confirmed histologically whenever possible.

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)

Bagegni N, Thomas S, Liu N, Luo J, Hoog J, Northfelt DW, Goetz MP, Forero A, Bergqvist M, Karen J, Neumuller M, Suh EM, Guo Z, Vij K, Sanati S, Ellis M, Ma CX. Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib. Breast Cancer Res. 2017 Nov 21;19(1):123. doi: 10.1186/s13058-017-0913-7.

Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine