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NCT Number: NCT03631953

Combination of Alpelisib and Trametinib in Progressive Refractory Meningiomas

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).

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Key information

Conditions

Meningioma Central Nervous System Neoplasms Meningeal Neoplasms Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Nerve Tissue Neoplasms, Vascular Tissue Nervous System Diseases Nervous System Neoplasms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Assistance Publique Hôpitaux de Marseille

Marseille, 13354, France

Location status: Recruiting

Location contact

Olivier CHINOT, PU-PH

CONTACT

[email protected]

491385545 ext. +33

Thomas GRAILLON, PH

CONTACT

[email protected]

491385545 ext. +33

Thomas GRAILLON, PH

PRINCIPAL_INVESTIGATOR

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Histologically proven meningioma grade I, II and III
  • Progression is defined as growing meningiomas on 2 different Magnetic Resonance Imaging (MRI) 3 to 6 months apart
  • Patients must have failed surgery, and not amenable to a new curative intended surgery
  • Patients must have failed radiotherapy and/or radiosurgery
  • Patients who have given their written consent
  • No contra indication to Alpelisib and Trametinib
  • No receiving other investigational agents
  • Written informed consent
  • Adequate bone marrow function
  • Adequate liver function as shown by
  • Adequate renal function

Exclusion criteria

  • Contra indication to Alpelisib and Trametinib
  • Women of child-bearing age who are using no effective means of contraception
  • Pregnant or breast-feeding women
  • Patients receiving other investigational agents
  • Known intolerance or hypersensitivity to Alpelisib and Trametinib
  • Uncontrolled diabetes mellitus
  • Patients who have any severe and uncontrolled medical condition
  • Patients receiving chronic treatment with immunosuppressives
  • Patients with a known history of HIV seropositivity
  • Patients who have a history of another primary malignancy less than or equal to 3 years, with
  • the exceptions of non-melanoma skin cancer, and carcinoma in situ of uterine cervix

Treatment and study plan

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.

Primary outcomes

  1. Dose Limiting Toxicity (DLT) rate of combination Alpelisib and Trametinib

    Time frame: 36 months

    Evaluate adverse events graded (toxicity) according to National Cancer Institute's Common Toxicity Criteria (version 4.0).

Study contacts

Contact information is provided by the study sponsor or research team.

Olivier CHINOT, PU-PH

CONTACT

[email protected]

491385545 ext. +33

Thomas GRAILLON, PH

CONTACT

[email protected]

491385545 ext. +33

Sponsors and collaborators

Lead sponsor

Assistance Publique Hopitaux De Marseille

Other

Registry information

Official study title

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

Acronym: ALTREM

Important dates

Study start
2019
Primary completion
2026
Study completion
2026
First posted
Aug 15, 2018
Registry last updated
Aug 6, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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