Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in Treating Participants with HR-Positive, HER2-Positive Metastatic Breast Cancer

Status: Active


This phase I / II trial studies the side effects and best dose of anastrozole, palbociclib, trastuzumab and pertuzumab and how well they work in treating participants with hormone receptor-(HR) positive, HER2-positive breast cancer that has spread to other locations in the body. Anastrozole and palbociclib are enzyme inhibitors that may stop the growth of tumor cells by blocking some of the enzymes needed cell growth. Monoclonal antibodies, such as trastuzumab and pertuzumab may interfere with the ability of tumor cells to grow and spread. Giving anastrozole, palbociclib, trastuzumab and pertuzumab may work better in treating participants with HR+, HER2+ metastatic breast cancer.

Eligibility Criteria

Inclusion Criteria

  • Women with metastatic breast cancer, measurable or evaluable disease including bone metastasis only (as per the Response Evaluation Criteria in Solid Tumors [RECIST] v1.1)
  • No prior systemic treatment for metastatic breast cancer
  • Pathologic confirmation of metastatic breast cancer diagnosed by core needle biopsy
  • Metastatic breast cancer with any evidence of estrogen receptor (ER) or progesterone receptor (PR) positivity in >= 1% cells in biopsy specimens from either a primary or metastatic site is eligible
  • Evidence of HER2 positive metastatic breast cancer in either a primary or metastatic site, if 3+ by an immunohistochemistry (IHC) method defined as uniform membrane staining for HER2 in 10% or more of tumor cells or demonstrate HER2 gene amplification by an in situ hybridization (ISH) method (single probe, average HER2 copy number >= 6.0 signals/cell; dual probe HER2/chromosome enumeration probe [CEP] 17 ratio >= 2.0 with an average HER2 copy number >= 4.0 signals/cell; dual probe HER2/CEP 17 ratio >= 2.0 with an average HER2 copy number < 4.0 signals/cell; and HER2/CEP17 ratio < 2.0 with an average HER2 copy number >= 6.0 signals/cell) or amplified by fluorescence in situ hybridization (FISH) > 2.0; high average copy number of HER2 (>= 6.0 signals/cell) is considered positive regardless of the HER2/CEP17 ratio
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2
  • Stable brain metastasis allowed (> 2 weeks, clinically stable post treatment with surgery +/- radiation or radiation alone and off steroids)
  • Transthoracic echocardiogram with ejection fraction > 50%
  • Postmenopausal status or receiving ovarian ablation with a gonadotropin-releasing hormone (GnRH) agonist such as goserelin or leuprolide; postmenopausal status is defined by any one of the following criteria: * Prior bilateral oophorectomy * Prior ovarian radiation for the purpose of ablation * Age >= 60 years * Age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, or ovarian suppression) and follicle stimulating hormones (FSH), luteinizing (LH), and estradiol in the postmenopausal range per local normal
  • Absolute neutrophil count (ANC) >= 1,500/mm^3 (=< 28 days prior to registration)
  • Platelet count >= 75,000/ mm^3 (=< 28 days prior to registration)
  • Hemoglobin (Hg) > 9 g/dL (=< 28 days prior to registration)
  • Total bilirubin =< 1.5 x upper limits of normal (ULN) (=< 28 days prior to registration)
  • Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (=< 5 x ULN in patients with liver metastasis) (=< 28 days prior to registration)
  • Creatinine =< 1.5 x ULN (=< 28 days prior to registration)
  • Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to the local regulatory requirements
  • A baseline computed tomography (CT) chest/abdomen/pelvis and bone scan or positron emission tomography (PET)/CT
  • Negative serum or urine pregnancy test within 7 days prior to starting treatment
  • Women of child-bearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 90 days following completion of therapy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * Note: Recommended methods of birth control are: The consistent use of an intrauterine device (IUD), double barrier methods (diaphragm with spermicidal gel or condoms with contraceptive foam), sexual abstinence (no sexual intercourse) or sterilization; men must agree to use a condom and not father a child for the duration of the study and for 90 days after completion of therapy

Exclusion Criteria

  • HER2 negative metastatic breast carcinoma defined as 0 or 1+ by IHC or with a FISH ratio (HER2 gene copy/ chromosome 17) < 2 if IHC 2+ by local institution standard protocol
  • Any prior treatment for metastatic breast cancer (excluding radiation therapy for the purpose of ovarian ablation). Note: prior adjuvant therapy with trastuzumab and pertuzumab is permitted after a 6-month window following completion of adjuvant therapy has passed
  • Patients currently receiving anticancer therapies or who have received anticancer therapies within 2 weeks of the start of study drug (including chemotherapy, radiation therapy, and biologics). Patients who have received prior endocrine therapy for fertility purposes will be eligible
  • Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study
  • Prior treatment with any investigational drug within the preceding 2 weeks
  • Co-administration with strong CYP3A4 inducers (e.g., phenytoin, rifampin, carbamazepine, St John’s Wort, bosentan, efavirenz, etravirine, modafinil, and nafcillin), strong CYP3A4 inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole), and CYP3A4 substrates (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus)
  • Uncontrolled brain metastases
  • Leptomeningeal metastases
  • Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin
  • Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as: * Symptomatic congestive heart failure of New York heart Association Class III or IV * Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease * Severely impaired lung function as defined as spirometry and diffusion capacity of the lung for carbon monoxide (DLCO) that is 50% of the normal predicted value and/or oxygen (O2) saturation that is 89% or less at rest on room air * Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN * Active (acute or chronic) or uncontrolled severe infections * Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of palbociclib (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
  • Patients with an active, bleeding diathesis
  • History of noncompliance to medical regimens
  • Patients unwilling to or unable to comply with the protocol
  • Ongoing alcohol or drug addiction
  • Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods; if barrier contraceptives are being used, these must be continued throughout the trial by both sexes; hormonal contraceptives are not acceptable as a method of contraception; (women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to starting treatment)

Locations & Contacts

New York

New York
Icahn School of Medicine at Mount Sinai
Status: Active
Contact: Amy Diane Tiersten
Phone: 212-241-3300
Laura and Isaac Perlmutter Cancer Center at NYU Langone
Status: In review
Contact: Sylvia Adams
Phone: 212-731-5795
Mount Sinai Chelsea
Status: Active
Contact: Paula Klein
Phone: 212-604-6021
Mount Sinai West
Status: Active
Contact: Anupama Goel
Phone: 212-523-8692
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Status: In review
Contact: Kevin Michael Kalinsky
Phone: 212-305-1945
NYP / Weill Cornell Medical Center
Status: In review
Contact: Eleni Andreopoulou
Phone: 212-821-0796

Trial Objectives and Outline


I. To determine the dose-limiting toxicity (DLT) and maximally tolerated dose (MTD) for palbociclib when administered in combination with anastrozole, trastuzumab and pertuzumab. (Phase I)

II. To determine the clinical benefit rate (CBR) of treatment with anastrozole, palbociclib, trastuzumab, and pertuzumab in HR+, HER2+ metastatic breast cancer patients. (Phase II)


I. To describe the adverse events associated with anastrozole, palbociclib, trastuzumab, and pertuzumab. (Phase I)

II. To determine progression free survival in HR+, HER2+ metastatic breast cancer patients treated with anastrozole, palbociclib, trastuzumab, and pertuzumab. (Phase II)

III. To determine the type, incidence, severity (as graded by the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version [v.] 4.0), seriousness and relationship to study medications of adverse events (AEs) and any laboratory abnormalities at the MTD. (Phase II)


I. To determine potential biomarkers of response to palbociclib including cyclin D1 expression levels, cytoplasmic cyclin E levels, phosphorylated retinoblastoma expression, retinoblastoma, p16 levels and CDKs 2, 4 and 6.

II. To determine potential mechanisms of resistance that may develop with treatment.

OUTLINE: This is a phase I, dose escalation study of palbociclib followed by a phase II study.

Participants receive anastrozole orally (PO) once daily (QD) on days 1-28, and palbociclib PO QD on days 1-21. Participants also receive trastuzumab intravenously (IV) over 30-90 minutes and pertuzumab IV over 30-60 minutes once every 21 days. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed-up at 30 days and then every 6 months for up to 2 years.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type


Lead Organization

Lead Organization
Icahn School of Medicine at Mount Sinai

Principal Investigator
Amy Diane Tiersten

Trial IDs

Primary ID 17-0919
Secondary IDs NCI-2018-00678 ID NCT03304080