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Alpha-TEA and Trastuzumab for the Treatment of Refractory HER2+ Metastatic Breast Cancer

Trial Status: Active

This phase I trial studies the side effects and best dose of alpha-TEA when given together with trastuzumab and to see how well they work for the treatment of HER2+ breast cancer that does not respond to treatment (refractory) and has spread to other places in the body (metastatic). Anti-cancer treatment, such as alpha-TEA, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Alpha-TEA may also alter cancer growth by stimulating the body’s immune response against the tumor. Trastuzumab is a form of “targeted therapy” because it works by attaching itself to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by the body’s immune system. Giving alpha-TEA and trastuzumab may work better for the treatment of HER2+ refractory and metastatic breast cancer compared to usual treatment.

Inclusion Criteria

  • Patients with progressive HER2/neu overexpressing metastatic breast, not considered curable by conventional therapies * HER2 positivity will be defined per the 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines (Journal of Clinical Oncology [JCO] 2018) * Extra-skeletal disease that can be accurately measured >= 10 mm by standard imaging techniques within 28 days of treatment
  • Patients must continue trastuzumab dosing per standard of care through the entire study period
  • Patients must have previously received trastuzumab/pertuzumab and trastuzumab emtansine (TDM-1) in the metastatic setting
  • Prior lapatinib in the metastatic setting is allowed, but not required
  • Patients with estrogen receptor (ER) and / or progesterone receptor (PR) positive metastatic breast cancer are eligible and may continue anti-estrogen therapy for the duration of the study
  • Patients must be at least 14 days post cytotoxic chemotherapy prior to enrollment
  • Patients must be at least 14 days post immunosuppressant prior to enrollment
  • Patients on bisphosphonates and/or endocrine therapy are eligible and can continue on this therapy concurrently
  • Women who are having sex that can lead to pregnancy must have a negative pregnancy test and must avoid becoming pregnant while on alpha-TEA and for 4 weeks after the last dose of alpha-TEA. Men must avoid fathering a child while on alpha-TEA and for 4 weeks after the last dose of alpha-TEA
  • Patients must have Eastern Cooperative Oncology Group (ECOG) performance status score of =< 2
  • Patients must have recovered from major infections and/or surgical procedures, and in the opinion of the investigator, not have significant active concurrent medical illnesses precluding study treatment
  • White blood cell (WBC) >= 2000/mm^3
  • Hemoglobin (Hgb) >= 8 mg/dl
  • Estimated creatinine clearance (Crcl) by the Cockcroft-Gault (C-G) equation >= 60 mL/min
  • Total bilirubin =< 1.5 x upper limit of normal
  • Aspartate aminotransferase (AST) < 1.5 X upper limit of laboratory normal
  • Alanine aminotransferase (ALT) < 1.5 X upper limit of laboratory normal
  • Alkaline phosphatase < 2.5 X upper limit of laboratory normal
  • International normalized ratio (INR) < 1.5
  • Prothrombin time (PT) < 16 seconds
  • Partial thromboplastin time (PTT) < 38 seconds
  • Ability to swallow capsules
  • Patients must have adequate cardiac function as demonstrated by normal left ventricular ejection fraction (LVEF) >= the lower limit of normal for the facility on multi-gated acquisition (MUGA) scan or echocardiogram (ECHO) within 3 months of enrollment. Must be off vitamin E supplements for at least two weeks prior to first dose of study drug

Exclusion Criteria

  • Patients with any of the following cardiac conditions: * Restrictive cardiomyopathy * Unstable angina within 6 months prior to enrollment * New York Heart Association functional class III-IV heart failure * Symptomatic pericardial effusion * Right atrial enlargement on ECHO would not be allowed
  • History of or active atrial fibrillation or supraventricular tachycardia
  • History of documented cardiac arrhythmia
  • Active cardiac ischemia. Patients with a history of ischemia ameliorated with stent placement or coronary artery bypass grafting and who have no evidence of ischemia by exercise or physiological stress testing are eligible
  • Patients with any clinically significant autoimmune disease requiring active treatment
  • Patients receiving any concurrent systemic immunosuppressants. Patients who require brief courses of steroids to manage allergic reaction to intravenous contrast used in radiographic studies are eligible
  • Patients receiving strong inhibitors or inducers of CYP3A4/5
  • Patients who are pregnant or breast-feeding
  • Patients who are simultaneously enrolled in other treatment studies
  • Active brain metastatic disease. Patients with brain metastases who have been treated with surgery, gamma-knife radiosurgery or radiation and no radiographic progression for at least 4 weeks and off steroids are eligible
  • Any medical or psychiatric condition that in the opinion of the principal investigator (PI) would preclude compliance with study procedures
  • Malabsorption state such as ulcerative colitis, previous surgical resection of > 20% of intestine or stomach
  • Surgery or severe trauma within 4 weeks of study entry (minimally invasive procedures acceptable)
  • Corrected QT interval (QTc) greater than 450 msec at (calculated using Bazett’s formula), sick-sinus syndrome or other active cardiac disease
  • Prior blood clot or need for ongoing anti-coagulation therapy
  • Patient with abnormal thyroid function or who are euthyroid but on medication for thyroid disorders must be excluded


Fred Hutch / University of Washington Cancer Consortium
Status: ACTIVE
Contact: William R. Gwin
Phone: 206-221-5956


I. To determine the safety of 4 escalating doses of alpha-tocopheryloxyacetic acid (alpha-TEA) therapy when combined with trastuzumab in patients with progressive metastatic HER2+ breast cancer.

II. To determine the clinical response rate of alpha-TEA therapy when combined with trastuzumab in patients with progressive metastatic HER2+ breast cancer.


I. To determine if concurrent alpha-TEA and trastuzumab increases the level of activated effector memory CD4+ and CD8+ T-cells at 4 escalating doses.

II. To determine if concurrent alpha-TEA and trastuzumab increases the number of HER2-specific T cells at each dose level.

III. To determine whether concurrent alpha-TEA and trastuzumab modulates the level and function of natural killer (NK) cells.


I. To evaluate if the presence of Tbet+ and GATA3+ CD4+ and CD8+ tumor infiltrating lymphocytes is associated with clinical response to concurrent alpha-TEA and trastuzumab therapy.

OUTLINE: This is a dose-escalation study of alpha-TEA.

Patients receive one of 4 doses of alpha-TEA orally (PO) on days 1-14. Patients also receive trastuzumab on day 1 of cycle 1 and then every 3 weeks per standard of care. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 4 years.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Fred Hutch / University of Washington Cancer Consortium

Principal Investigator
William R. Gwin

  • Primary ID RG1004302
  • Secondary IDs NCI-2019-06457
  • ID NCT04120246