Palbociclib, Letrozole, and Trastuzumab Emtansine in Treating Patients with Refractory HER2+ ER+ Metastatic Breast Cancer

Inclusion Criteria

• Ability to understand and the willingness to sign a written informed consent form
• Pathologically confirmed diagnosis of estrogen receptor (ER) positive and HER2 positive metastatic breast cancer based on local laboratory results. Estrogen receptor positive breast cancer is defined as >= 10%. HER2 positive breast cancer is defined as immunohistochemistry (IHC) score of 3+ or positive in situ hybridization (FISH) test per American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines
• Prior treatment with a taxane (including paclitaxel, docetaxel and/or nanoparticle protein-bound paclitaxel)
• Prior treatment with trastuzumab with or without pertuzumab
• Measurable or non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcl
• Hemoglobin >= 9.0 g/dL
• Total bilirubin =< 1.5 x institutional upper limit of normal
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
• Creatinine within normal institutional limits
• Cardiac ejection fraction >= 50% by either echocardiogram (ECHO) or multigated acquisition scan (MUGA)
• Women must be post-menopausal. Post-menopausal is defined as: * A woman who has undergone a bilateral oophorectomy (with or without hysterectomy), * Spontaneous cessation of menses for 12 consecutive months or more * No menses for < 12 consecutive months with follicle-stimulating hormone and estradiol levels in postmenopausal ranges according to institutional standards, * Has a history of a partial hysterectomy with follicle-stimulating hormone (FSH) and estradiol within postmenopausal ranges OR ovarian function suppressed with gonadotropin-releasing hormone (GnRH) agonists (negative human chorionic gonadotropin [HCG] required) with estradiol levels in the postmenopausal range, according to institutional standards
• Must be able to swallow pills (tablets [letrozole] and capsules [palbociclib])

Exclusion Criteria

• Current or anticipated use of other investigational agents
• Prior therapy with a cyclin-dependent kinase 4/6 inhibitor
• Subject has received chemotherapy or radiotherapy within 14 days prior to cycle 1, day 1 of the study or has not recovered from adverse events due to agents administered more than 14 days earlier
• Subject has symptomatic brain metastases. Subjects with asymptomatic or treated brain metastases are eligible. Must be off steroids for more than 14 days
• Patients with leptomeningeal disease will be excluded
• Current use or anticipated need for treatment with any medications or substances that are inhibitors or inducers of CYP3A4. Lists including medications and substances known or with the potential to interact with the CYP3A4 isoenzymes are provided
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to palbociclib or other agents used in study including T-DM1 and letrozole
• Peripheral neuropathy of >= 3 per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Subject has a concurrent malignancy or malignancy within 3 years of enrollment, with the exception of adequately treated non-melanoma skin cancer or curatively resected cervical cancer
• Known human immunodeficiency virus (HIV) infection
• Pregnant or nursing