Combination of Alpelisib and Trametinib in Progressive Refractory Meningiomas (ALTREM)

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

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).

Study Overview

• Status: Unknown
• Conditions: Meningioma
• Intervention / Treatment: Drug: Trametinib; Drug: Alpelisib; Biological: Blood sample; Device: MRI

• Study Type: Interventional
• Enrollment (Anticipated): 25
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Thomas GRAILLON, PH; Phone Number: +33 491385545; Email: thomas.graillon@ap-hm.fr
• Study Contact Backup: Name: Olivier CHINOT, PU-PH; Phone Number: +33 491385545; Email: olivier.chinot@ap-hm.fr

Study Locations

• France
  • Marseille, France, 13354
    • Recruiting
    • Assistance Publique Hopitaux de Marseille
    • Contact: Thomas GRAILLON, PH; Phone Number: +33 491385545; Email: thomas.graillon@ap-hm.fr
    • Contact: Olivier CHINOT, PU-PH; Phone Number: +33 491385545; Email: olivier.chinot@ap-hm.fr
    • Principal Investigator: Thomas GRAILLON, PH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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).	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Assistance Publique Hopitaux De Marseille
• Investigators: Study Director: Jean-Oliver ARNAUD, Director, Assistance Publique Hopitaux de Marseille

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2019
• Primary Completion (Anticipated): September 1, 2022
• Study Completion (Anticipated): September 1, 2022

Study Registration Dates

• First Submitted: August 13, 2018
• First Submitted That Met QC Criteria: August 13, 2018
• First Posted (Actual): August 15, 2018

Study Record Updates

• Last Update Posted (Actual): May 1, 2020
• Last Update Submitted That Met QC Criteria: April 29, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms, Vascular Tissue; Meningeal Neoplasms; Meningioma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Trametinib
• Other Study ID Numbers: 2018-05; RCAPHM18_0015 (Other Identifier: Sponsor's ID)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No