Study to Evaluate Biomarkers and Safety of Dapagliflozin Concomitant With Neoadjuvant Therapy

A Pilot Study to Evaluate Biomarkers and Safety of Dapagliflozin Concomitant With Neoadjuvant Therapy for Patient With HER2-negative Early-stage Breast Cancer and Hyperinsulinemia

The primary objective of the study is to assess metabolic plasma markers of insulin resistance in patients with early-stage HER2-negative breast cancers receiving dapagliflozin concomitant with neoadjuvant therapy.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; Hyperinsulinism; HER2-negative Breast Cancer
• Intervention / Treatment: Drug: Dapagliflozin 10mg

Detailed Description

This is a single arm, open label trial that will evaluate changes in plasma markers of insulin resistance, namely, fasting glucose and insulin, measured as the HOMA-IR score, as well as the safety of the addition of dapagliflozin to neoadjuvant treatment in hyperinsulinemic women with newly diagnosed early stage HER2-negative breast cancers who are candidates for neoadjuvant therapy.

Hypotheses are: (i) the SGLT2 inhibitor, dapagliflozin, administered concomitantly with weekly neoadjuvant therapy in hyperinsulinemic women with newly diagnosed HER2-negative breast cancers will lead to a decrease in fasting plasma insulin and glucose and thus, a downregulation in downstream insulin signaling in the tumor as measured by Protein kinase B (PKB)/AKT phosphorylation. (ii) that dapagliflozin can be safely coadministered at full dose with multiagent chemotherapy or chemo-immunotherapy.

Routine, standard of care neoadjuvant chemotherapy, with or without immunotherapy, will be given together with the investigational product. Acceptable chemotherapy regimens include: 1) weekly paclitaxel x12 treatments followed by every two-week doxorubicin, cyclophosphamide (ddAC) x 4 treatments (ddAC-T; ); 2) pembrolizumab every 3 weeks (Q3W), with carboplatin + weekly paclitaxel (cycles 1-4) x12 weeks followed by ddAC x 4 treatments (cycles 5-8) (KEYNOTE-522 regimen; only for participants with stage II-III ER/PR and HER-negative breast cancer); 3) docetaxel plus cyclophosphamide and 4) docetaxel plus carboplatin.

The primary objective of the study is to assess metabolic plasma markers of insulin resistance in participants with early-stage HER2-negative breast cancers receiving dapagliflozin concomitant with neoadjuvant therapy.

Secondary objectives are to assess tissue expression of insulin signaling intermediates and SGLT2 by immunohistochemistry (IHC) on pre- and post-treatment tissue samples.

Outcomes will be assessed before treatment and 12 weeks post treatment (after completion of all neoadjuvant therapy but before surgery).

Registration (including outcome measures) was updated to reflect current protocol July 2024.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Carl Brown; Phone Number: 475-241-1065; Email: carl.brown@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Recruiting
      • Yale Cancer Center Smilow Cancer Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Women > 18 years of age with newly diagnosed, histologically confirmed, clinical stage I-III, HER2-negative - either ER+ or triple negative - invasive breast cancer as defined by ASCO CAP guidelines for whom neoadjuvant chemotherapy would be indicated. The following chemotherapy regimens are acceptable:

  1. Weekly or dose dense paclitaxel, followed by dose dense doxorubicin plus cyclophosphamide
  2. Docetaxel plus cyclophosphamide
  3. Docetaxel plus carboplatin plus or minus pembrolizumab
  4. Paclitaxel plus carboplatin concurrent with every 3 week pembrolizumab followed by dose dense doxorubicin plus cyclophosphamide concurrent with every 3 week pembrolizumab (KEYNOTE-522 regimen; only for participants with triple negative breast cancer)
• BMI ≥ 25 kg/m2
• Hyperinsulinemia defined as HOMA-IR ≥ 2.5.
• Willing and able to provide written informed consent for the trial.
• Has at least one (1) physical 4-5-micron single H&E slide from diagnostic biopsy available
• Female participants of childbearing potential should have a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Female participants must be 1 year post-menopausal orsurgically sterile, Women of childbearing potential who are sexually active with a non-sterilized male partner must agree to follow their chemotherapy provider's instructions for birth control.

• Participants should have adequate organ function to tolerate chemotherapy, as defined by:

  1. peripheral granulocyte count of > 1,500/mm3
  2. platelet count > 100,000/mm3
  3. hemoglobin >9 g/dL
  4. total bilirubin < 1.5 x upper limit of normal (ULN)
  5. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) each < 1.5 x ULN
  6. serum creatinine < 1.5 x ULN
  7. INR/PT/PTT each < 1.5 x ULN
• Able to swallow oral formulation of the study agent
• Subjects should not donate blood while participating in this study, or for at least 90 days following the last dose of chemotherapy

Exclusion Criteria:

• Participants who underwent partial excisional biopsy or lumpectomy, segmental mastectomy or modified radical mastectomy or sentinel node biopsy and therefore cannot be assessed accurately for pathologic response, are not eligible.
• Participants currently pregnant or breastfeeding.
• Participants for whom any of the planned chemotherapies are contraindicated.
• Participants with currently diagnosed type I or II diabetes mellitus.
• Participants taking any antidiabetic medication that would affect insulin resistance or hyperinsulinemia (i.e. TZD, GLP-1RA, DPP-4i, SGLT2i, metformin) in the past one month.
• Participants with history of hypersensitivity reaction to dapagliflozin.
• Participants with eGFR < 25.
• History of recurrent (three or more occurrences within 12 months, or two or more occurrences within 6 months) urinary tract infections.
• Currently participating in weight loss programs or weight change in the past 3 months (> 5% current body weight) or have a history of gastrointestinal surgery.
• Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, intranasal influenza, rabies, BCG, and typhoid vaccine.
• Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dapagliflozin; All participants (with insulin resistance and Estrogen Receptor (ER)+HER2-negative or ER/Progesterone receptor (PR)/HER2-negative breast cancer) will receive current standard of care neoadjuvant chemotherapy as determined by the treating physician, plus dapagliflozin 10 mg orally taken daily throughout chemotherapy treatment.	Drug: Dapagliflozin 10mg; 10 mg tablets for oral administration daily throughout chemotherapy treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Homeostasis Model Assessment-Insulin Resistance (HOMA-IR)	Change in HOMA-IR (calculated as fasting insulin (μU/ml) x fasting glucose (mmol/l) divided by 22.5.	baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Fasting glucose concentration	Fasting plasma glucose concentration will be assessed following an overnight fast at baseline and 12 weeks post treatment	baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy
Change in Fasting insulin concentration	Fasting plasma insulin concentration will be assessed at baseline and 12 weeks post treatment	baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy
Total and phosphorylated PKB/AKT	Immunohistochemistry (IHC) staining for expression of Total and phosphorylated PKB/AKT in breast cancer tissue, before and after (in participants with residual cancer) treatment. For quantification of IHC, sections will be scored manually by a pathologist using the Allred system, a clinical instrument based on the percentage of cells that stain by immunohistochemistry for PKB/AKT (on a scale of 0 to 5) and the intensity of that staining (on a scale of 0 to 3, for a possible maximum total score of 8. The lower the number the less staining.	baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy
Total and phosphorylated insulin receptor	Immunohistochemistry (IHC) staining for expression of Total and phosphorylated insulin receptor in breast cancer tissue, before and after (in participants with residual cancer) treatment. For quantification of IHC, sections will be scored manually by a pathologist using the Allred system, a clinical instrument based on the percentage of cells that stain by immunohistochemistry for PKB/AKT (on a scale of 0 to 5) and the intensity of that staining (on a scale of 0 to 3, for a possible maximum total score of 8. The lower the number the less staining.	baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy
Total and phosphorylated insulin-like growth factor-1 receptor (IGF1R)	Immunohistochemistry (IHC) staining for expression of Total and phosphorylated insulin-like growth factor-1 receptor (IGF1R) in breast cancer tissue, before and after (in participants with residual cancer) treatment. For quantification of IHC, sections will be scored manually by a pathologist using the Allred system, a clinical instrument based on the percentage of cells that stain by immunohistochemistry for PKB/AKT (on a scale of 0 to 5) and the intensity of that staining (on a scale of 0 to 3, for a possible maximum total score of 8. The lower the number the less staining.	baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy
Total and phosphorylated insulin receptor substrate (IRS) 1	Immunohistochemistry (IHC) staining for expression of Total and phosphorylated insulin receptor substrate (IRS) 1 in breast cancer tissue, before and after (in participants with residual cancer) treatment. For quantification of IHC, sections will be scored manually by a pathologist using the Allred system, a clinical instrument based on the percentage of cells that stain by immunohistochemistry for PKB/AKT (on a scale of 0 to 5) and the intensity of that staining (on a scale of 0 to 3, for a possible maximum total score of 8. The lower the number the less staining.	baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy
Sodium-glucose cotransporter-2 (SGLT2)	Immunohistochemistry (IHC) staining for expression of SGLT2 in breast cancer tissue, before and after (in participants with residual cancer) treatment. For quantification of IHC, sections will be scored manually by a pathologist using the Allred system, a clinical instrument based on the percentage of cells that stain by immunohistochemistry for PKB/AKT (on a scale of 0 to 5) and the intensity of that staining (on a scale of 0 to 3, for a possible maximum total score of 8. The lower the number the less staining.	baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Maryam Lustberg, MD, MPH, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2024
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: August 3, 2023
• First Submitted That Met QC Criteria: August 3, 2023
• First Posted (Actual): August 14, 2023

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Metabolic Diseases; Glucose Metabolism Disorders; Skin Diseases; Breast Diseases; Nutritional and Metabolic Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Hyperinsulinism; Sodium-Glucose Transporter 2 Inhibitors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; dapagliflozin
• Other Study ID Numbers: 2000033529; No NIH funding (Other Identifier: 11.09.23)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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.: No