Dapagliflozin for the Treatment of Hyperinsulinemia in Patients Undergoing Neoadjuvant Therapy for HER2 Negative, Stage I-III Breast Cancer
This phase I trial tests the safety and side effects of dapagliflozin with chemotherapy before surgery (neoadjuvant therapy) for the treatment of high insulin levels (hyperinsulinemia) among patients with HER2 negative, stage I-III breast cancer. Tumors in people with high blood insulin levels might not respond as well to chemotherapy as tumors in people with normal insulin levels. Dapagliflozin is in a class of medications called sodium-glucose co-transporter 2 (SGLT2) inhibitors. It lowers blood sugar by causing the kidneys to get rid of more glucose in the urine. Giving dapagliflozin, together with chemotherapy, may lower blood sugar and insulin levels in patients with stage I-III breast cancer.
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 American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) guidelines for whom neoadjuvant chemotherapy would be indicated. The following chemotherapy regimens are acceptable: * Weekly or dose dense paclitaxel, followed by dose dense doxorubicin plus cyclophosphamide * Docetaxel plus cyclophosphamide * Docetaxel plus carboplatin plus or minus pembrolizumab * 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)
- Body mass index (BMI) ≥ 25 kg/m^2
- Hyperinsulinemia defined as homeostasis model assessment-insulin resistance (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 hematoxylin and eosin (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 or surgically 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
- Peripheral granulocyte count of > 1,500/mm^3
- Platelet count > 100,000/mm^3
- Hemoglobin > 9 g/dL
- Total bilirubin < 1.5 x upper limit of normal (ULN)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) each < 1.5 x ULN
- Serum creatinine < 1.5 x ULN
- International normalized ratio (INR)/prothrombin time (PT)/partial thromboplastin time (PTT) each < 1.5 x ULN
- Able to swallow oral formulation of the study agent
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 chemotherapies on protocol 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. thiazolidinedione [TZD], GLP-1RA, DPP-4i, SGLT2i, metformin) in the past one month
- Participants with history of hypersensitivity reaction to dapagliflozin
- Participants with estimated glomerular filtration rate (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, Bacille Calmette Guerin (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
Additional locations may be listed on ClinicalTrials.gov for NCT05989347.
Locations matching your search criteria
United States
Connecticut
Derby
Fairfield
Greenwich
Guilford
New Haven
North Haven
Stamford
Torrington
Trumbull
Waterbury
Waterford
Rhode Island
Westerly
PRIMARY OBJECTIVE:
I. To study blood-based biomarkers of insulin signaling in participants with early-stage estrogen receptor positive (ER+), HER2 negative (-), and triple negative breast cancers receiving dapagliflozin concomitant with neoadjuvant chemotherapy.
SECONDARY OBJECTIVE:
I. To assess tissue expression of insulin signaling intermediates and SGLT2 by immunohistochemistry (IHC) on pre- and post-treatment tissue samples.
EXPLORATORY OBJECTIVES:
I. To estimate the pathologic complete response (pCR) rate.
II. To estimate the distribution of residual cancer burden (RCB) index.
III. To assess tolerability and safety of adding dapagliflozin to chemotherapy by Common Terminology Criteria for Adverse Events (CTCAE), version (v) 5.0.
IV. To assess participant reported quality of life (QoL) measures during and immediately after treatment.
OUTLINE:
Patients receive standard of care (SOC) chemotherapy as determined by their treating oncologist. Starting on day 1 of SOC chemotherapy, patients receive dapagliflozin orally (PO) once daily (QD) for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients whose treatment regimen includes anthracyclines continue to receive dapagliflozin PO QD until 2 weeks following the last chemotherapy treatment in the absence of disease progression or unacceptable toxicity. Patients then undergo SOC surgery within 4 weeks of the last dose of chemotherapy. Patients undergo breast magnetic resonance imaging (MRI) and/or mammography and blood and urine sample collection throughout the study.
After completion of study treatment, patients are followed up at 2 weeks and within 30 days of surgery.
Trial PhasePhase I
Trial Typebasic science
Lead OrganizationYale University
Principal InvestigatorMaryam Beheshti Lustberg
- Primary ID2000033529
- Secondary IDsNCI-2025-02049
- ClinicalTrials.gov IDNCT05989347