A Phase II Randomized Study Evaluating the Biological and Clinical Effects of the Combination of Palbociclib With Letrozole as Neoadjuvant Therapy in Post-Menopausal Women With Estrogen-Receptor Positive Primary Breast Cancer
Condition: Breast Cancer; Breast Carcinoma; Breast Tumors
MeSH terms: Breast Neoplasms
Intervention: Letrozole; palbociclib
Intervention MeSH terms: Letrozole; Palbociclib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 307.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This study will look at effects the combination of palbociclib and letrozole may have on
      estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative
      breast cancer tumors which have not yet been treated. Letrozole is a type of endocrine
      therapy called an aromatase inhibitor (AI) and is standard treatment for post-menopausal
      women with ER-positive/HER2-negative breast cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must be postmenopausal women defined as: Age 56 or older with no spontaneous
             menses for at least 12 months prior to study entry; or Age 55 or younger with no
             menses for at least 12 months prior to study entry (e.g., spontaneous or secondary to
             hysterectomy) and with a documented estradiol level in the postmenopausal range
             according to local institutional/laboratory standard; or Age greater than or equal to
             18 with documented bilateral oophorectomy.

          -  Operable ER-positive/HER2- negative, invasive early breast cancer, suitable for
             neoadjuvant AI treatment. HER2-negative as determined by American Society of Clinical
             Oncology - College of American Pathologists (ASCO-CAP) guidelines.

          -  No known severe hypersensitivity reactions to compounds similar to palbociclib or
             palbociclib excipients or to endocrine treatments.

          -  A breast tumor with an ultrasound size of at least 2.0 cm.

          -  Patients must have the ability to swallow oral medication.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          -  At the time of randomization, blood counts performed within 4 weeks prior to
             randomization must meet the following criteria: absolute neutrophil count (ANC) must
             be greater than or equal to 1500/mm3; Platelet count must be greater than or equal to
             100,000/mm3; Hemoglobin must be greater than or equal to 10 g/dL.

          -  international normalized ratio (INR) must be within normal limits of the local
             laboratory ranges.

          -  The following criteria for evidence of adequate hepatic function performed within 4
             weeks prior to study entry must be met: total bilirubin must be less than or equal to
             upper limit of normal (ULN) for the lab unless the patient has a bilirubin elevation
             greater than ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome involving
             slow conjugation of bilirubin; and alkaline phosphatase must be must be less than or
             equal to 1.5 x ULN for the lab; and aspartate aminotransferase (AST) and alanine
             aminotransferase (ALT) must be less than or equal to 1.5 x ULN for the lab.

          -  Serum creatinine performed within 4 weeks prior to study entry must be less than or
             equal to 1.25 x ULN or estimated creatinine clearance less than 60 mL/min (as
             calculated using the method standard for the institutions).

        Exclusion Criteria:

          -  Active hepatitis B or hepatitis C with abnormal liver function tests.

          -  HIV positive patients receiving antivirals.

          -  Premenopausal or peri-menopausal women.

          -  Inflammatory/inoperable breast cancer.

          -  HER2-positive as determined using ASCO-CAP Guidelines.

          -  Concurrent use (defined as use within 4 weeks prior to baseline tissue sample being
             taken) of hormone replacement therapy (HRT) or any other estrogen-containing
             medication (including vaginal estrogens)

          -  Prior endocrine therapy for breast cancer.

          -  Any invasive malignancy within previous 5 years (other than basal cell carcinoma or
             cervical carcinoma in situ).

          -  Other nonmalignant systemic disease that would preclude the patient from receiving
             study treatment or would prevent required follow up such as: Active infection or
             chronic infection requiring chronic suppressive antibiotics; Malabsorption syndrome,
             ulcerative colitis, inflammatory bowel disease, resection of the stomach or small
             bowel, or other disease or condition significantly affecting gastrointestinal
             function; Chronic daily treatment with corticosteroids with a dose of greater than or
             equal to 10 mg/day methylprednisolone equivalent (excluding inhaled steroids); Seizure
             disorders requiring medication.

          -  Diagnosis by fine needle aspiration (FNA) alone or excisional biopsy or lumpectomy
             performed prior to study entry.

          -  Surgical axillary staging procedure prior to study procedure (with exception of FNA or
             core biopsy).

          -  Definitive clinical or radiologic evidence of metastatic disease.

          -  History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral
             ductal carcinoma in situ (DCIS) treated with radiotherapy or contralateral invasive
             breast cancer at any time.

          -  Any treatment, including radiotherapy, chemotherapy, and/or targeted therapy,
             administered for the currently diagnosed breast cancer prior to study entry.

          -  Use of any medication or substances that are strong inhibitors or inducers of CYP3A
             isoenzymes.

          -  Class III or Class IV myocardial disease as described by the New York Heart
             Association; a recent history (within 6 months) of myocardial infarction, or
             symptomatic arrhythmia at the time of randomization. Class III: Patients with cardiac
             disease resulting in marked limitation of physical activity. Such patients are
             comfortable at rest. Less than ordinary physical activity that causes fatigue,
             palpitation, dyspnea, or anginal pain. Class IV: Patients with cardiac disease
             resulting in inability to perform any physical activity without discomfort. Symptoms
             of cardiac insufficiency or anginal syndrome may be present even at rest.

          -  QTc greater than 480 msec or a family or personal history of long or short QT
             syndrome, Brugada syndrome or know history of QTc prolongation, or Torsade de Pointes
             (TdP).

          -  The investigator should assess the patient to determine if she has any psychiatric or
             addictive disorder or other condition that, in the opinion of the investigator, would
             preclude her from meeting the study requirements.