Combination of Alpelisib and Trametinib in Progressive Refractory Meningiomas

Sponsor
Assistance Publique Hopitaux De Marseille
Study ID
NCT03631953
Phase
PHASE1
Status
Recruiting
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Conditions

  • Meningioma

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

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

Study Details

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).

Key Dates

Start date
Sep 30, 2019
Status verified
Aug 2024
Primary completion
Jan 29, 2026
Completion
Jan 29, 2026

Study Design

Enrollment
25 participants (estimated)
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT

Arms

  • Experimental: Alpelisib in combination with Trametinib administered
    A panel of 3 doses of Alpelisib could be tested in combination with fixed dose of Trametinib (1.5 mg every day).

Primary Outcome Measure

Dose Limiting Toxicity (DLT) rate of combination Alpelisib and Trametinib [ Time Frame: 36 months ]

Central Contacts

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