Ignite Creation Date:
2024-05-06 @ 4:33 PM
Last Modification Date:
2024-10-26 @ 2:12 PM
Study NCT ID:
NCT05025735
Status:
UNKNOWN
Last Update Posted:
2021-10-19
First Post:
2021-06-26
Brief Title:
Alpelisib Fulvestrant and Dapagliflozin for the Treatment of HR HER2 - PIK3CA Mutant Metastatic Breast Cancer
Sponsor:
Saint Lukes Health System
Organization:
Saint Lukes Health System
Study Overview
Official Title:
Alpelisib Fulvestrant and Dapagliflozin for the Treatment of HR HER2 - PIK3CA Mutant Metastatic Breast Cancer
Status:
UNKNOWN
Status Verified Date:
2021-10
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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 HRHER2- 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
Detailed Description:
Alpelisib is a p110α specific PI3K inhibitor that has shown significant clinical benefit in patients with HRHER2 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 57 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-719alpelisib 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 levels3
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
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-719alpelisib 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 levels3
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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None