NCT05025735

Alpelisib, Fulvestrant and Dapagliflozin for the Treatment of HR+, HER2 -, PIK3CA Mutant Metastatic Breast Cancer

• Status: Unknown
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 25 (estimated)
• Sponsor: Saint Luke's Health System · Academic / Other
• Sex: All
• Age: 18 Years – 65 Years
• Healthy volunteers: Not accepted

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 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.

Detailed 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.

Conditions

• Metastatic Breast Cancer
• HER2-negative Breast Cancer

Interventions

Type	Name	Description
DRUG	Dapagliflozin 10Mg Tab	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. If concurrent treatment with dapagliflozin can abrogate the alpelisib induced hyperglycemia and subsequent rebound hyperinsulinemia it may significantly improve the therapeutic efficacy of alpelisib.

Timeline

• Start date: 2021-08-25
• Primary completion: 2022-12-01
• Completion: 2023-07-01
• First posted: 2021-08-27
• Last updated: 2021-10-19

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study