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

Primary Purpose

Breast Cancer, ER Positive Breast Cancer

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Letrozole 2.5mg
Sponsored by
Dartmouth-Hitchcock Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Cancer focused on measuring Letrozole, Aromatase Inhibitor

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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.

Sites / Locations

  • Dartmouth Hitchcock Medical Center
  • Dartmouth-Hitchcock Medical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment

Arm Description

Letrozole 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.

Outcomes

Primary Outcome Measures

Change in Tumor CPT1-alpha levels
Determine whether residual cancer cells exhibit upregulation of the fatty acid transport CPT1-alpha (compared to baseline)

Secondary Outcome Measures

Proportion of subjects who experience Clinical Response
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.
Change in tumor CPT1-alpha histoscore
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.
Change in tumor mitochondrial content per cell
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.
Change in tumor ACC histoscore
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.
Change in tumor FASN histoscore
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.
Change in tumor CD36 histoscore
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.
Change in tumor lipid droplet content per cell
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.

Full Information

First Posted
September 22, 2020
Last Updated
December 19, 2022
Sponsor
Dartmouth-Hitchcock Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT04568616
Brief Title
Neoadjuvant ArOMatase Inhibitor Therapy for ER+ Breast Cancer (NAOMI)
Acronym
NAOMI
Official Title
Phase II Study of Neoadjuvant ArOMatase Inhibitor Therapy for ER+ Breast Cancer (NAOMI)
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Recruiting
Study Start Date
August 13, 2021 (Actual)
Primary Completion Date
September 2023 (Anticipated)
Study Completion Date
September 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Dartmouth-Hitchcock Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer, ER Positive Breast Cancer
Keywords
Letrozole, Aromatase Inhibitor

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
28 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment
Arm Type
Experimental
Arm Description
Letrozole 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.
Intervention Type
Drug
Intervention Name(s)
Letrozole 2.5mg
Other Intervention Name(s)
Femara
Intervention Description
Aromatase Inhibitor
Primary Outcome Measure Information:
Title
Change in Tumor CPT1-alpha levels
Description
Determine whether residual cancer cells exhibit upregulation of the fatty acid transport CPT1-alpha (compared to baseline)
Time Frame
Baseline to 4-12 Weeks
Secondary Outcome Measure Information:
Title
Proportion of subjects who experience Clinical Response
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.
Time Frame
4 to12 Weeks
Title
Change in tumor CPT1-alpha histoscore
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.
Time Frame
Baseline to 4 -12 weeks
Title
Change in tumor mitochondrial content per cell
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.
Time Frame
Baseline to 4 -12 weeks
Title
Change in tumor ACC histoscore
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.
Time Frame
Baseline to 4 -12 weeks
Title
Change in tumor FASN histoscore
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.
Time Frame
Baseline to 4 -12 weeks
Title
Change in tumor CD36 histoscore
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.
Time Frame
Baseline to 4 -12 weeks
Title
Change in tumor lipid droplet content per cell
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.
Time Frame
Baseline to 4 -12 weeks

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. The invasive cancer must be estrogen receptor alpha (ER)-positive, with ER staining present in greater than 50% of invasive cancer cells by IHC. 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). 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. 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. 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. 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. Ability to give informed consent. Exclusion Criteria: 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. Any other neoadjuvant therapy for breast cancer. Bisphosphonate treatment for bone symptoms is allowed. Women who are pregnant or lactating.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Research Nurse
Phone
1-800-639-6918
Email
Cancer.Research.Nurse@dartmouth.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mary D Chamberlin, MD
Organizational Affiliation
Dartmouth-Hitchcock Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dartmouth Hitchcock Medical Center
City
Lebanon
State/Province
New Hampshire
ZIP/Postal Code
03756
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mary D Chamberlin, MD
Phone
800-639-6918
Email
mary.d.chamberlin@hitchcock.org
First Name & Middle Initial & Last Name & Degree
Research Nurse
Phone
800-639-6918
Email
cancer.research.nurse@dartmouth.edu
Facility Name
Dartmouth-Hitchcock Medical Center
City
Lebanon
State/Province
New Hampshire
ZIP/Postal Code
03756
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Research Nurse, RN
Phone
800-639-6918
Email
Cancer.Research.Nurse@Dartmouth.edu
First Name & Middle Initial & Last Name & Degree
Mary D Chamberlin, MD

12. IPD Sharing Statement

Learn more about this trial

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

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