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

Status: Active

Description

This phase I / II trial studies best dose of palbociclib and how well it works in combination with letrozole and trastuzumab emtansine in treating patients with HER2 positive (+) estrogen receptor (ER)+ breast cancer that has spread to other places in the body and has not responded to treatment. Palbociclib and letrozole may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as trastuzumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving palbociclib, letrozole, and trastuzumab may work better in treating patients with HER2+ ER+ breast cancer.

Eligibility Criteria

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

Locations & Contacts

Kansas

Kansas City
University of Kansas Cancer Center
Status: Active
Contact: Lauren Nye
Phone: 913-574-0085
Email: lnye@kumc.edu
University of Kansas Cancer Center-West
Status: Active
Contact: Lauren Nye
Phone: 913-574-0085
Email: lnye@kumc.edu
Overland Park
University of Kansas Cancer Center-Overland Park
Status: Active
Contact: Lauren Nye
Phone: 913-574-0085
Email: lnye@kumc.edu
Westwood
University of Kansas Hospital-Westwood Cancer Center
Status: Active
Contact: Lauren Nye
Phone: 913-574-0085
Email: lnye@kumc.edu

Missouri

Kansas City
The University of Kansas Cancer Center-North
Status: Active
Contact: Lauren Nye
Phone: 913-574-0085
Email: lnye@kumc.edu
Lee's Summit
The University of Kansas Cancer Center-Lee's Summit
Status: Active
Contact: Lauren Nye
Phone: 913-574-0085
Email: lnye@kumc.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the phase II recommended dose of palbociclib in combination with letrozole and trastuzumab emtansine (T-DM1). (Phase I)

II. To characterize the anti-neoplastic activity of the combination of palbociclib, letrozole and T-DM1 in estrogen receptor positive, HER2 positive advanced and metastatic breast cancer. (Phase II)

SECONDARY OBJECTIVES:

I. To characterize the safety and tolerability of palbociclib in combination with letrozole and T-DM1.

EXPLORATORY OBJECTIVES:

I. To explore the role of serum thymidine kinase 1 activity (a marker of proliferation), tumor gene expression signature and tumor expression of retinoblastoma (Rb), retinoblastoma-associated protein (pRb), cyclin D1 and p16 (CDKN2A) in tumor response.

II. To explore the pharmacokinetics of palbociclib, letrozole and mertansine (the cytotoxic microtubule inhibitor function of T-DM1) in combination.

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

Patients receive palbociclib orally (PO) once daily (QD) on days 1-21, letrozole PO QD on days 1-21, and trastuzumab emtansine intravenously (IV) over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, and then every 9 weeks thereafter.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
University of Kansas Cancer Center

Principal Investigator
Lauren Nye

Trial IDs

Primary ID 2017-IIT-HER2-Aspire
Secondary IDs NCI-2019-00381
Clinicaltrials.gov ID NCT03709082