Clinical Trials

Patients who were pre-registered to NCI 9170 trial (Phase II Trial of Neoadjuvant MK-2206 in Combination with either Anastrozole if Postmenopausal or Anastrozole and Goserelin if Premenopausal in Women with Clinical Stage 2 or 3 PIK3CA Mutant Estrogen Receptor Positive and HER2 Negative Invasive Breast Cancer), started anastrozole (or anastrozole plus goserelin if premenopausal) < 6 weeks, and were found negative for PIK3CA hotspot mutations are eligible to be screened for the wild type cohort. In institutions without NCI9170 open, or after completion of enrollment to NCI9170 in institutions where it is open, patients will be pre-registered to this trial and those with PIK3CA mutations will be enrolled to the PIK3CA mutant cohort. Pre-registration is not required for patients to be enrolled in the endocrine resistant cohort, as PIK3CA mutation status will not be assessed.

Pre-Registration Inclusion Criteria:

• 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.
• If premenopausal, patient must be willing to comply with pregnancy requirements
• Adequate organ and marrow function as defined below:
  • leukocytes ≥ 3,000/mcL
  • absolute neutrophil count ≥ 1,500/mcL
  • platelets ≥ 100,000/mcL
  • total bilirubin ≤ upper normal institutional limits
  • AST(SGOT)/ and ALT(SGPT) ≤ 2.5 X institutional upper limit normal
  • Creatinine ≤ upper normal institutional limits
• Able to understand and willing to sign an IRB-approved written informed consent document.

Pre-Registration Exclusion Criteria:

• 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.
  
  NOTE: HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with PD 0332991. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
   
• Evidence of inflammatory cancer (clinical presentation of skin erythema involving more than one third of the breast or pathological evidence of dermal lymphatic involvement)
• 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.

Registration Inclusion Criteria

The criteria below must be met for registration onto the study in addition to the pre-registration criteria, except treatment with endocrine therapy for this cancer is allowed prior to registration.

• For the PIK3CA mutant cohort: tumor PIK3CA mutation present
• For the PIK3CA wild type cohort: tumor PIK3CA mutation absent.
  
  Note that if a patient did not have sufficient tissue for PIK3CA sequencing at pre-registration or if PIK3CA sequencing result is delayed, she could be registered and enrolled on this 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.
   
• In premenopausal women, serum estradiol level in postmenopausal range ≤ 7 days prior to registration.
• 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.
  • Note that enrollment to the endocrine resistant cohort will depend on the funding availability. Please contact the study chair before enrolling patients to this cohort.

Registration Exclusion Criteria

The criteria below must be met for registration onto the study 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).