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

Study Overview
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Brief Summary
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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.

Detailed Description
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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: (i) assess changes in the levels of additional plasma markers of insulin signaling from baseline (before treatment), to during (on-treatment) and immediately after neoadjuvant therapy (post-treatment), and (ii) assess tissue expression of insulin signaling intermediates and SGLT2 by immunohistochemistry (IHC) on pre- on- 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).

Official Title
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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

Conditions
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Breast Cancer, Hyperinsulinism, HER2-negative Breast Cancer

Intervention / Treatment
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* Drug: Dapagliflozin 10mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women with newly diagnosed, histologically confirmed, clinical stage I-III, HER2-negative, invasive breast cancer as defined by ASCO CAP guidelines for whom neoadjuvant chemotherapy would be indicated. The following chemotherapy regimens are acceptable Weekly paclitaxel, followed by dose dense doxorubicin plus cyclophosphamide Docetaxel plus cyclophosphamide Docetaxel plus carboplatin 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/assent for the trial. Has sufficient archival breast cancer tissue available from the diagnostic biopsy OR if not, is willing to undergo a baseline core needle ultrasound guided breast research biopsy for biomarker analysis prior to day 1 of study. Willing to undergo an on-treatment research tumor biopsy after 12 weeks of treatment. Female participants of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication given that all participants will be receiving cytotoxic chemotherapy as part of the treatment regimen, the effects of which can be harmful for the developing fetus. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. All participants of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Non-childbearing potential in women is defined as postmenopausal status without menses for at least 1 year and an FSH value in the postmenopausal range and/or status post hysterectomy, oophorectomy or tubal ligation. Participants should have adequate organ function to tolerate chemotherapy, as defined by: peripheral granulocyte count of > 1,500/mm3 platelet count > 100,000/mm3 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 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Interventional Model Description: Women with BMI ≥ 25 kg/m2 and hyperinsulinemia (HOMA-IR ≥ 2.5) and early stage, operable HER2-negative (by FISH or IHC 0, 1+ or 2+) breast cancer for whom systemic neoadjuvant chemotherapy is indicated.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin<br>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<br>* 10 mg tablets for oral administration daily throughout chemotherapy treatment<br>|

What is the study measuring?
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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 | 
| Change in Insulin-like growth factor-1 (IGF-1) concentration | Plasma IGF-1 concentration will be assessed during an oral glucose tolerance test at baseline and 12 weeks post treatment | baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy | 
| Change in Hemoglobin A1c concentration | Plasma hemoglobin A1c concentration will be assessed during an oral glucose tolerance test at baseline and 12 weeks post treatment | baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy | 
| Change in plasma Leptin concentration | Plasma Leptin concentration will be assessed during an oral glucose tolerance test at baseline and 12 weeks post treatment | baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy | 
| Change in Adiponectin concentration | Plasma Adiponectin concentration will be assessed during an oral glucose tolerance test at baseline and 12 weeks post treatment | baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy | 
| Change in Beta-hydroxybuterate concentration | Plasma Beta-hydroxybuterate concentration will be assessed during an oral glucose tolerance test 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 |