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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04120246
Recruitment Status : Recruiting
First Posted : October 9, 2019
Last Update Posted : October 29, 2021
Sponsor:
Collaborator:
Veana Therapeutics, Inc.
Information provided by (Responsible Party):
University of Washington

Tracking Information
First Submitted Date  ICMJE October 7, 2019
First Posted Date  ICMJE October 9, 2019
Last Update Posted Date October 29, 2021
Actual Study Start Date  ICMJE April 8, 2020
Estimated Primary Completion Date February 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 7, 2019)
  • Incidence of adverse events of 4 escalating doses of alpha-tocopheryloxyacetic acid (TEA) therapy when combined with trastuzumab [ Time Frame: Up to 4 years ]
    Toxicity grading will be evaluated per Cancer Therapy Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events (CTCAE) 5.0.
  • Clinical response rate of alpha-TEA when combined with trastuzumab [ Time Frame: Up to 4 years ]
    Clinical response will be performed by computed tomography (CT) scan of the chest, abdomen, and pelvis performed prior to enrollment and then after every 3 cycles per standard of care. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and immune related (ir)RECIST criteria will be used to determine response. Both progression free survival (PFS) and overall survival (OS) will be measured.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 28, 2020)
  • 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 ]
    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-.
  • Change in the number of HER2 specific T cells at each dose level [ Time Frame: Baseline up to 4 years ]
    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.
  • 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 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 7, 2019)
  • Change in level of activated effector memory CD4+ and CD8+ T-cells at 4 escalating doses of alpha-TEA and concurrent trastuzumab [ Time Frame: Baseline up to 4 years ]
    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-.
  • Change in the number of HER2 specific T cells at each dose level [ Time Frame: Baseline up to 4 years ]
    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.
  • Modulation of circulating natural killer (NK) cells with concurrent alpha-TEA and trastuzumab therapy [ Time Frame: Up to 4 years ]
    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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Alpha-TEA and Trastuzumab for the Treatment of Refractory HER2+ Metastatic Breast Cancer
Official Title  ICMJE A Phase I Dose Escalation Trial of Alpha-Tocopheryloxyacetic Acid (α-TEA) in Patients With Treatment Refractory HER2+ Metastatic Breast Cancer
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Anatomic Stage IV Breast Cancer AJCC v8
  • HER2 Positive Breast Carcinoma
  • Metastatic Breast Carcinoma
  • Prognostic Stage IV Breast Cancer AJCC v8
  • Refractory Breast Carcinoma
Intervention  ICMJE
  • Drug: Alpha-tocopheryloxyacetic Acid
    Given PO
    Other Names:
    • 12-trimethyltridecyl) chroman-6-yloxy) Acetic Acid
    • a-TEA
    • alpha-TEA
  • Biological: Trastuzumab
    Given IV
    Other Names:
    • 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
Study Arms  ICMJE Experimental: Treatment (alpha-TEA, trastuzumab)
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.
Interventions:
  • Drug: Alpha-tocopheryloxyacetic Acid
  • Biological: Trastuzumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 7, 2019)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 1, 2024
Estimated Primary Completion Date February 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: William Gwin 206-221-5956 wrgwin@seattlecca.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04120246
Other Study ID Numbers  ICMJE RG1004302
NCI-2019-06457 ( Registry Identifier: NCI / CTRP )
8790 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of Washington
Study Sponsor  ICMJE University of Washington
Collaborators  ICMJE Veana Therapeutics, Inc.
Investigators  ICMJE
Principal Investigator: William Gwin Fred Hutch/University of Washington Cancer Consortium
PRS Account University of Washington
Verification Date October 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP