Palbociclib, Letrozole, and Trastuzumab before Surgery in Treating Patients with Estrogen Receptor Positive and HER2 Positive Stage II-III Breast Cancer

Status: Active


This phase II trial studies how well palbociclib, letrozole, and trastuzumab work before surgery in treating patients with estrogen receptor (ER) positive and HER2 positive stage II-III breast cancer. Palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs, such as letrozole, may lessen the amount of estrogen made by the body. Monoclonal antibodies, such as trastuzumab, may interfere with the ability of tumor cells to grow and spread. Giving palbociclib, letrozole, and trastuzumab before surgery may work better in treating patients with breast cancer.

Eligibility Criteria

Inclusion Criteria

  • Newly diagnosed clinical stage II or III ER+/HER2+ breast cancer with complete surgical excision of the breast cancer after neoadjuvant therapy as the treatment goal, staging criteria is to be based on American Joint Committee on Cancer (AJCC) 7
  • Tumor size at least 2 cm in one dimension by clinical or radiographic exam (World Health Organization [WHO] criteria); patients with histologically confirmed palpable lymph nodes may be enrolled regardless of breast tumor size
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< institutional upper limit of normal (IULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x IULN
  • Creatinine =< IULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Left ventricular ejection fraction (LVEF) >= 50% by transthoracic echocardiogram or multigated acquisition scan (MUGA)
  • Baseline corrected QT interval (corrected QT interval by Fridericia's formula [QTcF]) < 480 ms
  • Women of childbearing potential must agree to undergo pregnancy testing within 14 days of study entry and agree to use adequate contraception (barrier method of birth control, abstinence, not hormonal) prior to study entry and for the duration of study participation as well as chemical luteinizing hormone-releasing hormone (LHRH) agonist with goserelin; should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
  • Ability to understand and willingness to sign an Institutional Review Board (IRB) approved written informed consent document (or that of legally authorized representative, if applicable)

Exclusion Criteria

  • Prior systemic therapy for indexed breast cancer
  • Indeterminate or negative HER2 status
  • Inflammatory breast cancer
  • A history of other malignancy =< 5 years from diagnosis of indexed breast cancer (BC) with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix
  • Currently receiving any other investigational agents or received any within the past 28 days
  • Know to be human immunodeficiency virus (HIV) positive
  • Known hepatitis B or C infection
  • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to palbociclib, letrozole, trastuzumab, any other aromatase inhibitor, any other monoclonal antibody, or other agents used in the study
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia
  • 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)
  • Any condition that impairs the ability to swallow or absorb oral medication (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affective absorption)
  • Pregnant and/or breastfeeding; women of childbearing potential must have a negative pregnancy test within 14 days of study entry

Locations & Contacts


Saint Louis
Siteman Cancer Center at Washington University
Status: Active
Contact: Foluso Olabisi Ademuyiwa
Phone: 314-454-8313

New York

Roswell Park Cancer Institute
Status: Active
Contact: Ellis G. Levine
Phone: 716-845-2880

Trial Objectives and Outline


I. To determine the pathologic complete response (pCR) rate in patients with clinical stages II/III ER-positive (+) HER2+ breast cancer treated with neoadjuvant letrozole, trastuzumab, and palbociclib.


I. To assess safety and tolerability of palbociclib in combination with neoadjuvant letrozole and trastuzumab.

II. To assess the patient reported outcomes associated with palbociclib in combination with neoadjuvant letrozole and trastuzumab.


I. To determine if bone marrow disseminated tumor cells (DTC) status is a good indicator of clinical response and if subpopulations of DTCs emerge with neoadjuvant treatment.

II. To assess intrinsic breast cancer subtype utilizing complementary deoxyribonucleic acid (cDNA) microarray and to correlate with treatment response.

III. To examine the pharmacodynamic effect of the study drug treatment by proteomic and immunohistochemistry analysis of baseline, 2-week and surgical tumor sample, and to correlate with treatment response.

IV. To examine the mutational profiles by whole exome or targeted gene sequencing at baseline and at time of definitive surgery to correlate with treatment response.

V. To assess tumor cell apoptosis index post 2 weeks of palbociclib in combination with letrozole and trastuzumab.

VI. To examine markers of cell proliferation, apoptosis and senescence on 2-week biopsies as predictors of surgical outcome.

VII. To assess serum, plasma, and circulating tumor DNA (ctDNA) sequencing of selected genes, including ESR1, TP53, PIK3CA and retinoblastoma (RB), at baseline, and surgery to correlate with response.


Patients receive palbociclib orally (PO) daily on days 1-21, letrozole PO once daily (QD) on days 1-28, and trastuzumab intravenously (IV) over 30-90 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Within 6 weeks after the end of course 4, patients undergo surgery. Courses with letrozole continue until the day of surgery, and courses with trastuzumab continue every 3 weeks until the day of surgery.

After completion of study treatment, patients are followed up for 30-60 days and then yearly for 5 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type


Lead Organization

Lead Organization
Siteman Cancer Center at Washington University

Principal Investigator
Foluso Olabisi Ademuyiwa

Trial IDs

Primary ID 201610019
Secondary IDs NCI-2016-01516 ID NCT02907918