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This will be a single arm, open label pilot to test the combination of dapagliflozin, a commercially available SGLT-2 inhibitor, in combination with alpelisib + fulvestrant in patients with HR+/HER2- mBC. The objective of this study is to determine if the addition of dapagliflozin to the combination of alpelisib and fulvestrant leads to significant reduction in all-grade hyperglycemia.
Full description
Alpelisib is a p110α specific PI3K inhibitor that has shown significant clinical benefit in patients with HR+/HER2 negative mBC harboring activating PIK3CA mutations. The SOLAR-1 study randomized patients with MBC progressing after aromatase inhibitor therapy patients had a PFS of 11 months with fulvestrant plus alpelisib versus 5.7 months with fulvestrant alone. Alpelisib was associated with a 65% incidence of hyperglycemia, including 37% Grade 3 or 4 hyperglycemia.
Hyperglycemia is an expected effect of PI3K inhibitors given the pivotal role of PI3K in mediating the response to insulin in multiple tissues. Blocking insulin signaling by p110α inhibitors leads to glycogen breakdown in the liver along with decreased glucose uptake in peripheral tissues. The resulting hyperglycemia causes a compensatory response of increase insulin secretion by the pancreas.
Cantley and colleagues have shown in animal models that treatment with BYL-719(alpelisib) results in rapid increase in plasma glucose level and a compensatory increase in insulin.
They went on to show that this rebound hyperinsulinemia was able to rescue KPC tumor allografts from BYL-719 inhibition as evidenced by increasing phosphorylation of downstream effectors in the PI3K pathway, pAKT and PS6. Pretreatment of the mice with an SGLT-2 inhibitor decreased the hyperglycemia and hyperinsulinemia following treatment with BYL-719. Importantly, the response of the KPC tumor allografts to treatment was concordant with reduction in insulin levels.3
This provides a rationale for combining dapagliflozin with alpelisib in the treatment of HR+, PIK3CA mutant MBC. If concurrent treatment with dapagliflozin can abrogate the alpelisib induced hyperglycemia and subsequent rebound hyperinsulinemia it may significantly improve the therapeutic efficacy of alpelisib.
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Inclusion criteria
Patients > 18 years old with stage IV or locally advanced, unresectable Stage III breast cancer that is:
If female, post-menopausal status as defined by
PIK3CA activating mutation identified by a either in a CLIA certified tumor genomic assay or ctDNA assay.
Patients may be:
ECOG performance status 0-2
Patient has adequate bone marrow and organ function as defined by the following laboratory values:
Fasting plasma glucose (FPG) ≤ 200 and Glycosylated Hemoglobin (HbA1c) ≤ 6.5%
Fasting Serum amylase ≤ 2 × ULN
Fasting Serum lipase ≤ ULN
Exclusion criteria
Patient has not recovered from all toxicities related to prior anticancer therapies to NCI CTCAE version 4.03 Grade ≤1. Exception to this criterion: patients with any grade of alopecia are allowed to enter the study.
Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's best judgment.
Patients with Type I diabetes or history of diabetic ketoacidosis
Patient has received prior treatment with chemotherapy in the metastatic setting, fulvestrant, any PI3K, mTOR or AKT inhibitor
Patient has a known hypersensitivity to alpelisib or fulvestrant, or to any of the excipients of alpelisib or fulvestrant.
Patient is concurrently using other anti-cancer therapy.
Patient has had surgery within 14 days prior to starting study drug or has not recovered from major side effects of surgery.
Patient has central nervous system (CNS) involvement that does not meet ALL of the following criteria:
Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
Patient is following a ketogenic diet and unwilling to change diet.
Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, contraindicate patient participation in the clinical study.
Patient has currently documented pneumonitis (the chest CT scan performed at baseline for the purpose of tumor assessment should be reviewed to confirm that there are no relevant pulmonary complications present).
Patient is currently receiving or has received systemic corticosteroids 7 days prior to starting study drug, or who have not fully recovered from side effects of such treatment.
Note: The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular).
Sexually active males unless they are sterilized (at least 6 months prior to screening) or use a condom during intercourse while taking drug and for at least 8 months after stopping alpelisib and/or fulvestrant. .
Participation in a prior investigational study within 14 days prior to the start of study treatment or within 5 half-lives of the investigational product, whichever is longer.
Not able to understand and to comply with study instructions and requirements.
History of acute pancreatitis within1 year of screening or past medical history of chronic pancreatitis.
Primary purpose
Allocation
Interventional model
Masking
25 participants in 1 patient group
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Central trial contact
Kelley Aldrich, RN
Data sourced from clinicaltrials.gov
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