NCT03631953

Combination of Alpelisib and Trametinib in Progressive Refractory Meningiomas

Combination of Alpelisib and Trametinib in Progressive Refractory Meningiomas: Phase 1 Study

• Status: Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 25 (estimated)
• Sponsor: Assistance Publique Hopitaux De Marseille · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

Aggressive growing meningiomas resistant to multiple surgeries and radiotherapy constitute an unmet pharmaceutical need in neurooncology, leading to a fatal issue within a few months. Grade II-III meningiomas progression-free survival (PFS) 6 is at 10-15%. Median PFS grade III meningioma is approximate 3 years. Alpelisib is a well-tolerated Phosphoinositide 3-kinase α (Pi3Kα) specific inhibitor. However, phosphatidylinositol-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) inhibition does not induce apoptosis in vitro and induces an antiproliferative effect without any radiologic response in most treated patients. Trametinib, a mekinist (MEK) inhibitor is currently used in combined treatment for recurrent melanomas in clinical practice with a good clinical tolerance at 1-2 mg daily. In vitro, on meningioma primary cell culture, Trametinib induces cell apoptosis via caspase activity. These results strongly suggest the relevance to combine Alpelisib and Trametinib in aggressive and recurrent meningiomas. Alpelisib and Trametinib combination has not been studied to date, despite each drugs have been separately studied in phase 3. Multicenter, open label, dose-finding phase I study of Alpelisib in combination with Trametinib administered at a fixed dose (1.5 mg daily), both drugs will be administered daily. Starting dose of Alpelisib will be 160mg/day and will be increased to 200mg/day or decreased to 120mg/day depending of grade 3-4 adverse events occurrence, to determine maximal tolerated dose (MTD) and recommended dose. Primary Objective is to determine the safety profile and tolerability of Alpelisib and Trametinib given in combination in patients with aggressive and refractory meningiomas in terms of Dose-Limiting Toxicities (DLT, assessed during cycle 1).

Conditions

• Meningioma

Interventions

Type	Name	Description
DRUG	Trametinib	Trametinib administered at a fixed dose (1.5 mg daily)
DRUG	Alpelisib	A panel of 3 doses of ALPELISIB could be tested
BIOLOGICAL	Blood sample	Therapeutic biomarkers
DEVICE	MRI	A MRI with contrast will be performed before treatment start. Assessment of tumor growth.

Timeline

• Start date: 2019-09-30
• Primary completion: 2026-01-29
• Completion: 2026-01-29
• First posted: 2018-08-15
• Last updated: 2024-08-06

Locations

1 site across 1 country: France