Description:
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.
Title
- Brief Title: Alpha-TEA and Trastuzumab for the Treatment of Refractory HER2+ Metastatic Breast Cancer
- Official Title: A Phase I Dose Escalation Trial of Alpha-Tocopheryloxyacetic Acid (α-TEA) in Patients With Treatment Refractory HER2+ Metastatic Breast Cancer
Clinical Trial IDs
- ORG STUDY ID:
RG1004302
- SECONDARY ID:
NCI-2019-06457
- SECONDARY ID:
P30CA015704
- SECONDARY ID:
8790
- NCT ID:
NCT04120246
Conditions
- Anatomic Stage IV Breast Cancer AJCC v8
- HER2 Positive Breast Carcinoma
- Metastatic Breast Carcinoma
- Prognostic Stage IV Breast Cancer AJCC v8
- Refractory Breast Carcinoma
Interventions
Drug | Synonyms | Arms |
---|
Alpha-tocopheryloxyacetic Acid | 12-trimethyltridecyl) chroman-6-yloxy) Acetic Acid, a-TEA, alpha-TEA | Treatment (alpha-TEA, trastuzumab) |
Trastuzumab | 180288-69-1, 688097, ABP 980, Anti-c-ERB-2, Monoclonal Antibody, Anti-ERB-2, Anti-erbB2 Monoclonal Antibody, Anti-HER2/c-erbB2 Monoclonal Antibody, HER2 Monoclonal Antibody, Herceptin, Herceptin Trastuzumab Biosimilar PF-05280014, Herzuma, MoAb HER2, Monoclonal Antibody HER2, Ogivri, Ontruzant, RO0452317, Trastuzumab Biosimilar ABP 980, Trastuzumab Biosimilar HLX02, Trastuzumab Biosimilar PF-05280014, Trastuzumab Biosimilar SB3, Trastuzumab-DTTB, Trazimera, Kanjinti, Trastuzumab Biosimilar GB221 | Treatment (alpha-TEA, trastuzumab) |
Purpose
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.
Detailed Description
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 Arms
Name | Type | Description | Interventions |
---|
Treatment (alpha-TEA, trastuzumab) | Experimental | Patients receive one of 4 doses of alpha-TEA 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. | - Alpha-tocopheryloxyacetic Acid
- Trastuzumab
|
Eligibility Criteria
Inclusion Criteria:
- Patients with 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 with or without pertuzumab dosing per standard of
care through the entire study period
- 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 (within 28 days prior to first treatment)
- Hemoglobin (Hgb) >= 8 mg/dl (within 28 days prior to first treatment)
- Estimated creatinine clearance (Crcl) by the Cockcroft-Gault (C-G) equation >= 60
mL/min (within 28 days prior to first treatment)
- Total bilirubin =< 1.5 x upper limit of normal (within 28 days prior to first
treatment)
- Aspartate aminotransferase (AST) < 1.5 X upper limit of laboratory normal (within 28
days prior to first treatment)
- Alanine aminotransferase (ALT) < 1.5 X upper limit of laboratory normal (within 28
days prior to first treatment)
- Alkaline phosphatase < 2.5 X upper limit of laboratory normal (within 28 days prior to
first treatment)
- International normalized ratio (INR) < 1.5 (within 28 days prior to first treatment)
- Prothrombin time (PT) < 16 seconds (within 28 days prior to first treatment)
- Partial thromboplastin time (PTT) < 38 seconds (within 28 days prior to first
treatment)
- 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
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Incidence of adverse events of 4 escalating doses of alpha-tocopheryloxyacetic acid (TEA) therapy when combined with trastuzumab |
Time Frame: | Up to 4 years |
Safety Issue: | |
Description: | Toxicity grading will be evaluated per Cancer Therapy Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events (CTCAE) 5.0. |
Secondary Outcome Measures
Measure: | Change in level of activated effector memory CD4+ and CD8+ T-cells at 4 escalating doses of alpha-TEA and concurrent trastuzumab |
Time Frame: | At baseline, at cycle 4 Day 1, and then Day 1 of every 4th cycle while on study (each cycle is 28 days), assessed up to 4 years |
Safety Issue: | |
Description: | The level of memory CD4+ and CD8+ T cells will be evaluated by flow cytometry. Memory CD4+ T cells will be defined as CD3+CD4+CD38+HLA-DR+CCR7-CD45RA- and memory CD8+ T cells will be defined as CD3+CD8+CD38+ HLA-DR+CCR7-CD45RA-. |
Measure: | Change in the number of HER2 specific T cells at each dose level |
Time Frame: | Baseline up to 4 years |
Safety Issue: | |
Description: | Will determine if concurrent alpha-TEA and trastuzumab increase the number of HER2 specific T cells at each dose level. Endogenous immunity to HER2 will be evaluated using interferon (IFN)-gamma enzyme-linked immunosorbent spot (ELISPOT) assay. A statistically significant increase of HER2 specific immunity after concurrent alpha-TEA and trastuzumab treatment when compared to baseline will constitute augmentation of HER2 specific immunity. |
Measure: | Modulation of circulating natural killer (NK) cells with concurrent alpha-TEA and trastuzumab therapy |
Time Frame: | At baseline, at cycle 4 Day 1, and then Day 1 of every 4th cycle while on study (each cycle is 28 days), assessed up to 4 years |
Safety Issue: | |
Description: | Flow cytometry will be used to assess the number of NK cells as defined by CD3-CD16+CD56+ cells from whole blood. Flow will be used to analyze the function of NK cells, specifically through degranulation markers (CD107a+) and through IFN-gamma production. The level of NK cell CD107+ uptake and IFN-gamma production in response to major histocompatibility complex (MHC) class 1 negative cell will be evaluated. |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | University of Washington |
Trial Keywords
- Breast
- HER2+
- metastatic
- refractory
- immunotherapy
Last Updated
April 28, 2021