Alpha-TEA and Trastuzumab for the Treatment of Refractory HER2+ Metastatic Breast Cancer
- 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
- 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
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
Fred Hutch / University of Washington Cancer Consortium
William R. Gwin
- Primary ID RG1004302
- Secondary IDs NCI-2019-06457
- Clinicaltrials.gov ID NCT04120246