Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in HR-positive, HER2-positive Metastatic Breast

NCT03304080 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: GCO 17-0919
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 5

Brief Summary

This is a multicenter, phase I/II trial of anastrozole, palbociclib, trastuzumab, and pertuzumab is proposed as first-line therapy in metastatic hormone receptor-positive, HER2-positive breast cancer patients. In this phase I/II clinical trial, the researchers aim to establish the safety and efficacy of dual HER2 therapy in combination with palbociclib and anastrozole, which represents a novel and all biologic approach to the treatment of HR+, HER2+ metastatic breast cancer. Additionally, the researchers aim to examine potential biomarkers of response to palbociclib including cyclin D1, cyclin E1 and cyclin E2 expression levels, CDK 2, 4, and 6 levels, phosphorylated retinoblastoma expression and p16 levels. The researchers intend to use RNA sequencing to assess for other predictors of response in an unbiased manner to see if this correlates with inhibition of Ki-67 and phosphorylated retinoblastoma expression as well as evaluate for potential mechanisms of resistance.

Conditions

Breast Neoplasms; Breast Diseases

Keywords

Breast Neoplasms; Breast Diseases; Palbociclib; Trastuzumab; Pertuzumab; Hormone Antagonists; Anastrozole; Arimidex; Ibrance; Perjeta

Outcome Measures

Primary Outcomes (3)

• Dose-Limiting Toxicity (DLT)

  The dose-limiting toxicity (DLT) for palbociclib when administered in combination with anastrozole, trastuzumab and pertuzumab. A DLT will be defined as: * Grade 3 or 4 non-hematologic toxicity * Grade 3 neutropenia lasting greater than 21 days * Grade 3 or 4 neutropenia with neutropenic fever or * Grade 4 hematologic toxicity events experienced within the first 4 weeks (1 cycle) of study treatment. These will be assessed via the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI's CTCAE) v4.0 toxicity criteria.

  up to 3 months

• Maximum Tolerated Dose (MTD)

  The maximum tolerated dose (MTD) for palbociclib when administered in combination with anastrozole, trastuzumab and pertuzumab. If \> 33 % of patients experience a dose limiting toxicity (DLT) at any dose level, the dose level below that level will be considered the MTD. Or if the highest level has been reached and ≤ 33% of patients have experienced dose limiting toxicity (DLT), that will be considered the MTD.

  up to 3 months

• Clinical Benefit Rate (CBR)

  CBR will be measured by the percentage of patients whose cancer shrinks or remains stable over the duration of the study. This will be measured as the sum of complete response, partial response, and stable disease for greater than or equal to 6 months.

  average of 6 months

Secondary Outcomes (2)

• Progression Free Survival

  2 years

• Incidence of adverse events

  2 years

Study Arms (1)

HR-positive, Her2-positive Metastatic Breast Cancer

EXPERIMENTAL

Women and men with HR-positive, HER2-positive Metastatic Breast Cancer on trial of anastrozole, palbociclib, trastuzumab and pertuzumab

Drug: Anastrozole; Drug: Palbociclib; Drug: Trastuzumab; Drug: Pertuzumab

Interventions

Anastrozole DRUG

1 mg orally daily, day 1 to day 28

Also known as: Arimidex

HR-positive, Her2-positive Metastatic Breast Cancer

Palbociclib DRUG

Dose I: 100 mg orally daily, day 1 to day 21, then 7 days off in a 28 day cycle (Phase 1 only) Dose II: 125 mg orally daily, day 1 to day 21, then 7 days off in a 28 day cycle

Also known as: Ibrance

HR-positive, Her2-positive Metastatic Breast Cancer

Trastuzumab DRUG

8 mg/kg IV initial loading dose, followed by 6 mg/kg IV every 21 days

Also known as: Herceptin

HR-positive, Her2-positive Metastatic Breast Cancer

Pertuzumab DRUG

840 mg IV followed by a maintenance dose of 420 mg IV every 21 days

Also known as: Perjeta

HR-positive, Her2-positive Metastatic Breast Cancer

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Women or men 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 ER or PR positivity in ≥ 1% cells in biopsy specimens from either a primary or metastatic site
• Evidence of HER2 positive metastatic breast cancer in either a primary or metastatic site, if 3+ by an IHC method defined as uniform membrane staining for HER2 in 10% or more of tumor cells or demonstrate HER2 gene amplification by an ISH method (single probe, average HER2 copy number ≥6.0 signals/cell; dual probe HER2/CEP17 ratio ≥2.0 with an average HER2 copy number ≥4.0 signals/cell; dual probe HER2/chromosome enumeration probe (CEP) 17 ratio ≥2.0 with an average HER2 cop number \<4.0 signals/cell; and HER2/CEP17 ratio \<2.0 with an average HER2 copy number ≥6.0 signals/cell) or amplified by FISH \> 2.0. High average copy number of HER2 (≥6.0 signals/cell) is considered positive regardless of the HER2/CEP17 ratio.
• Women or men 18 years and older
• 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 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 FSH, LH, and estradiol in the postmenopausal range per local normal.
• 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

You may not qualify if:

• 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). For a current table of Substrates, Inhibitors and Inducers please access the following website:http://www.fda.gov/Drugs/DevelopmentApprovalProcess/" See Appendix C.
• 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 DLCO that is 50% of the normal predicted value and/or 02 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

Sponsors & Collaborators

• Icahn School of Medicine at Mount Sinai: lead
• Herbert Irving Comprehensive Cancer Center: collaborator
• Weill Medical College of Cornell University: collaborator
• NYU Langone Health: collaborator

Study Sites (5)

Mount Sinai Beth Israel Comprehensive Cancer Center West

New York, New York, 10011, United States

Location

Perlmutter Cancer Center NYU Langone

New York, New York, 10016, United States

Location

Mount Sinai West

New York, New York, 10019, United States

Location

New York Presbyterian Columbia Irving Comprehensive Cancer Center

New York, New York, 10032, United States

Location

New York Presbyterian Weill Cornell Medical Center

New York, New York, 10065, United States

Location

MeSH Terms

Conditions

Breast Neoplasms; Breast Diseases

Interventions

Anastrozole; palbociclib; Trastuzumab; pertuzumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Amy Tiersten, MD

  Icahn School of Medicine at Mount Sinai

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: October 3, 2017
• First Posted: October 6, 2017
• Study Start: December 20, 2017
• Primary Completion (Estimated): July 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: July 18, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share

Locations

US (5)