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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03631953
Recruitment Status : Unknown
Verified April 2020 by Assistance Publique Hopitaux De Marseille.
Recruitment status was:  Recruiting
First Posted : August 15, 2018
Last Update Posted : May 1, 2020
Sponsor:
Information provided by (Responsible Party):
Assistance Publique Hopitaux De Marseille

Study Description
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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).


Condition or disease Intervention/treatment Phase
Meningioma Drug: Trametinib Drug: Alpelisib Biological: Blood sample Device: MRI Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Combination of Alpelisib and Trametinib in Progressive Refractory Meningiomas: Phase 1 Study
Actual Study Start Date : September 30, 2019
Estimated Primary Completion Date : September 1, 2022
Estimated Study Completion Date : September 1, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Trametinib

Arms and Interventions
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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.


Outcome Measures
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Primary Outcome Measures :
  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).


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03631953


Contacts
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Contact: Thomas GRAILLON, PH 491385545 ext +33 thomas.graillon@ap-hm.fr
Contact: Olivier CHINOT, PU-PH 491385545 ext +33 olivier.chinot@ap-hm.fr

Locations
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France
Assistance Publique Hôpitaux de Marseille Recruiting
Marseille, France, 13354
Contact: Thomas GRAILLON, PH    491385545 ext +33    thomas.graillon@ap-hm.fr   
Contact: Olivier CHINOT, PU-PH    491385545 ext +33    olivier.chinot@ap-hm.fr   
Principal Investigator: Thomas GRAILLON, PH         
Sponsors and Collaborators
Assistance Publique Hopitaux De Marseille
Investigators
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Study Director: Jean-Oliver ARNAUD, Director Assistance Publique Hôpitaux de Marseille
More Information
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Responsible Party: Assistance Publique Hopitaux De Marseille
ClinicalTrials.gov Identifier: NCT03631953    
Other Study ID Numbers: 2018-05
RCAPHM18_0015 ( Other Identifier: Sponsor's ID )
First Posted: August 15, 2018    Key Record Dates
Last Update Posted: May 1, 2020
Last Verified: April 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Meningioma
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
Trametinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action