Clinical Trials /

Neoadjuvant ArOMatase Inhibitor Therapy for ER+ Breast Cancer (NAOMI)

NCT04568616

Description:

This is a single-arm, open-label study testing the effects of neoadjuvant therapy with the aromatase inhibitor letrozole in post-menopausal women with Stage I-III ER+, HER2- breast cancer. Eligible subjects will be treated with letrozole therapy for 4 to 12 weeks prior to surgical resection of the tumor. Tumor specimens obtained at baseline (diagnostic biopsy) and at surgery (surgical specimen) will be compared using molecular analyses. A subset of subjects will be asked to provide an optional research tumor biopsy prior to treatment for molecular analysis.

Related Conditions:
  • Invasive Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant ArOMatase Inhibitor Therapy for ER+ Breast Cancer (NAOMI)
  • Official Title: Phase II Study of Neoadjuvant ArOMatase Inhibitor Therapy for ER+ Breast Cancer (NAOMI)

Clinical Trial IDs

  • ORG STUDY ID: D20148
  • NCT ID: NCT04568616

Conditions

  • Breast Cancer
  • ER Positive Breast Cancer

Interventions

DrugSynonymsArms
Letrozole 2.5mgFemaraTreatment

Purpose

This is a single-arm, open-label study testing the effects of neoadjuvant therapy with the aromatase inhibitor letrozole in post-menopausal women with Stage I-III ER+, HER2- breast cancer. Eligible subjects will be treated with letrozole therapy for 4 to 12 weeks prior to surgical resection of the tumor. Tumor specimens obtained at baseline (diagnostic biopsy) and at surgery (surgical specimen) will be compared using molecular analyses. A subset of subjects will be asked to provide an optional research tumor biopsy prior to treatment for molecular analysis.

Detailed Description

      Approximately 70% of breast cancers express estrogen receptor alpha (ER), which is activated
      by estrogens and typically drives cancer cell growth. Adjuvant therapy with anti-estrogens
      such as tamoxifen and aromatase inhibitors (AIs) is commonly used to inhibit ER to prevent
      cancer (re)growth after early-stage breast tumors are surgically removed. However, ~33% of
      such patients (~300,000 new cases per year worldwide) will eventually develop
      anti-estrogen-resistant breast cancer that is metastatic or locally advanced; at this stage,
      the disease is almost never cured using available therapies and is uniformly fatal.
      Therefore, more effective treatment early in the course of disease (i.e., in the adjuvant
      setting, shortly after surgical removal of a tumor) has huge potential to prevent cancer
      regrowth.

      Most often, ER+ breast cancers re-emerge in the years after the end of the standard five-year
      anti-estrogen treatment regimen (called 'late recurrence'). Recent data indicate that
      continued anti-estrogen therapy in patients who remain "disease-free" after five years of
      anti-estrogen therapy modestly prevents cancer recurrence. However, tumor cells are
      detectable in bone marrow of patients who are "disease-free." Thus, anti-estrogen therapy in
      "disease-free" patients likely suppresses the growth of undetectable tumor cells, keeping
      them in a "clinically dormant" state (i.e., undetectable by standard clinical methods).
      Little is known about how such dormant cancer cells survive. This clinical study will help
      identify the signaling pathways essential for the survival of clinically dormant ER+ breast
      cancer cells to enable the development of more effective therapies to eradicate such cells
      and prevent cancer recurrence.
    

Trial Arms

NameTypeDescriptionInterventions
TreatmentExperimentalLetrozole 2.5mg tablet administered once daily for 4 to ~12 weeks (window of + 4 weeks for surgical scheduling flexibility) final dose taken the day of surgery.
  • Letrozole 2.5mg

Eligibility Criteria

        Inclusion Criteria:

          1. Histologic documentation of invasive breast cancer by core needle or incisional
             biopsy. Excess baseline biopsy tumor tissue sufficient to make ten 5-micron sections
             must be available for research use as part of this study.

          2. The invasive cancer must be estrogen receptor alpha (ER)-positive, with ER staining
             present in greater than 50% of invasive cancer cells by IHC.

          3. The invasive cancer must be HER2-negative (IHC 0-1+, or with a FISH ratio of <1.8 if
             IHC is 2+ or if IHC has not been done).

          4. Clinical Stage I-III invasive breast cancer with the intent to treat with surgical
             resection of the primary tumor. Baseline tumor must be ≥1 cm to provide adequate
             tissue.

          5. Patients with multicentric or bilateral disease are eligible if the subject is a
             candidate for clinically indicated neoadjuvant endocrine therapy. Samples from all
             available tumors are requested for research purposes.

          6. Women over 18 years of age, for whom neoadjuvant treatment with an aromatase inhibitor
             would be clinically indicated. Women must be surgically, medically, or naturally
             post-menopausal.

          7. Patients must meet the following clinical laboratory criteria:

               -  Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet count ≥ 75,000/mm3.

               -  Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN).

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN.

          8. Ability to give informed consent.

        Exclusion Criteria:

          1. Prior endocrine therapy for any histologically-confirmed cancer is not allowed. Prior
             endocrine therapy that was administered ≥5 years ago for the prevention of breast
             cancer in patients with no history of breast cancer is allowed.

          2. Any other neoadjuvant therapy for breast cancer. Bisphosphonate treatment for bone
             symptoms is allowed.

          3. Women who are pregnant or lactating.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Change in Tumor CPT1-alpha levels
Time Frame:Baseline to 4-12 Weeks
Safety Issue:
Description:Determine whether residual cancer cells exhibit upregulation of the fatty acid transport CPT1-alpha (compared to baseline)

Secondary Outcome Measures

Measure:Proportion of subjects who experience Clinical Response
Time Frame:4 to12 Weeks
Safety Issue:
Description:Determine the proportion of subjects who experience clinical response, defined as a ≥50% decrease in the longest dimension of the primary tumor. The longest dimension(s) of the primary tumor(s) will be measured from radiological images acquired as per standard of care before (up to 4 wk prior to) neoadjuvant letrozole treatment, and after neoadjuvant letrozole treatment (prior to surgery). If multiple primary tumors are detected, the sum of the longest diameters will be used to provide a single measurement at each time point for each subject. Pre- and post-treatment tumor lengths will be compared.
Measure:Change in tumor CPT1-alpha histoscore
Time Frame:Baseline to 4 -12 weeks
Safety Issue:
Description:Determine whether residual cancer cells exhibit altered levels of CPT1-alpha compared to baseline tumors. Specimens will be immunofluorescently stained using an antibody against CPT1-alpha. CPT1-alpha histoscore levels will be measured using Halo software to determine whether post-neoadjuvant therapy cancer cells exhibit increased levels compared to baseline cancer cells.
Measure:Change in tumor mitochondrial content per cell
Time Frame:Baseline to 4 -12 weeks
Safety Issue:
Description:Determine whether residual cancer cells exhibit altered mitochondrial length compared to baseline tumors. Specimens will be immunofluorescently stained using an antibody against TOM20. TOM20-stained organelle length per cell will be measured using Halo software to determine whether post-neoadjuvant therapy cancer cells exhibit increased mitochondrial content compared to baseline cancer cells.
Measure:Change in tumor ACC histoscore
Time Frame:Baseline to 4 -12 weeks
Safety Issue:
Description:Determine whether residual cancer cells exhibit altered levels of ACC compared to baseline tumors. Specimens will be immunofluorescently stained using an antibody against ACC. ACC levels will be measured using Halo software to determine whether post-neoadjuvant therapy cancer cells exhibit increased levels compared to baseline cancer cells.
Measure:Change in tumor FASN histoscore
Time Frame:Baseline to 4 -12 weeks
Safety Issue:
Description:Determine whether residual cancer cells exhibit altered levels of FASN compared to baseline tumors. Specimens will be immunofluorescently stained using an antibody against FASN. FASN levels will be measured using Halo software to determine whether post-neoadjuvant therapy cancer cells exhibit increased levels compared to baseline cancer cells.
Measure:Change in tumor CD36 histoscore
Time Frame:Baseline to 4 -12 weeks
Safety Issue:
Description:Determine whether residual cancer cells exhibit altered levels of CD36 compared to baseline tumors. Specimens will be immunofluorescently stained using an antibody against CD36. CD36 levels will be measured using Halo software to determine whether post-neoadjuvant therapy cancer cells exhibit increased levels compared to baseline cancer cells.
Measure:Change in tumor lipid droplet content per cell
Time Frame:Baseline to 4 -12 weeks
Safety Issue:
Description:Determine whether residual cancer cells exhibit altered lipid droplet content compared to baseline tumors. Specimens will be immunofluorescently stained using an antibody against perilipin. Perilipin-stained organelle content per cell will be measured using Halo software to determine whether post-neoadjuvant therapy cancer cells exhibit increased lipid droplet content compared to baseline cancer cells.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Dartmouth-Hitchcock Medical Center

Trial Keywords

  • Letrozole
  • Aromatase Inhibitor

Last Updated

September 24, 2020