Clinical Trials /

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

NCT04120246

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. 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 breast cancer compared to usual treatments.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

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
  • NCT ID: NCT04120246

Conditions

  • Anatomic Stage IV Breast Cancer AJCC v8
  • ERBB2 Overexpression
  • HER2 Positive Breast Carcinoma
  • Metastatic Breast Carcinoma
  • Prognostic Stage IV Breast Cancer AJCC v8
  • Refractory Breast Carcinoma

Interventions

DrugSynonymsArms
Alpha-tocopheryloxyacetic Acid12-trimethyltridecyl) chroman-6-yloxy) Acetic Acid, a-TEA, alpha-TEATreatment (alpha-TEA, trastuzumab)
Trastuzumab180288-69-1, 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, TrazimeraTreatment (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). Drugs used in chemotherapy, 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. 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 breast cancer compared to usual treatments.

Detailed Description

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

      Patients receive 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

NameTypeDescriptionInterventions
Treatment (alpha-TEA, trastuzumab)ExperimentalPatients receive 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 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 (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:Baseline 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: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:Not yet recruiting
Lead Sponsor:University of Washington

Trial Keywords

  • Breast - Female
  • Breast - Male

Last Updated