Combination of Alpelisib and Trametinib in Progressive Refractory Meningiomas

NCT03631953 | Recruiting Phase 1

• 2 other identifiers: 2018-05RCAPHM18_0015
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief 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

Outcome Measures

Primary Outcomes (1)

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

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

  36 months

Study Arms (1)

Alpelisib in combination with Trametinib administered

EXPERIMENTAL

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

Drug: Trametinib; Drug: Alpelisib; Biological: Blood sample; Device: MRI

Interventions

Trametinib DRUG

Trametinib administered at a fixed dose (1.5 mg daily)

Alpelisib in combination with Trametinib administered

Alpelisib DRUG

A panel of 3 doses of ALPELISIB could be tested

Alpelisib in combination with Trametinib administered

Blood sample BIOLOGICAL

Therapeutic biomarkers

Alpelisib in combination with Trametinib administered

MRI DEVICE

A MRI with contrast will be performed before treatment start. Assessment of tumor growth.

Alpelisib in combination with Trametinib administered

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Assistance Publique Hopitaux De Marseille: lead

Study Sites (1)

Assistance Publique Hôpitaux de Marseille

Marseille, 13354, France

RECRUITING

MeSH Terms

Conditions

Meningioma

Interventions

trametinib; Alpelisib; Blood Specimen Collection

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Jean-Oliver ARNAUD, Director

  Assistance Publique Hôpitaux de Marseille

  STUDY DIRECTOR

Central Study Contacts

Thomas GRAILLON, PH

CONTACT

491385545; thomas.graillon@ap-hm.fr

Olivier CHINOT, PU-PH

CONTACT

491385545; olivier.chinot@ap-hm.fr

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 13, 2018
• First Posted: August 15, 2018
• Study Start: September 30, 2019
• Primary Completion: January 29, 2026
• Study Completion: January 29, 2026
• Last Updated: August 6, 2024

Record last verified: 2024-08

Locations

FR (1)