Combination of Alpelisib and Trametinib in Progressive Refractory Meningiomas (ALTREM)
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|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
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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 Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||25 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
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).
Trametinib administered at a fixed dose (1.5 mg daily)
A panel of 3 doses of ALPELISIB could be tested
Biological: Blood sample
A MRI with contrast will be performed before treatment start. Assessment of tumor growth.
- 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).
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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
- 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
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
|Contact: Thomas GRAILLON, PH||491385545 ext +email@example.com|
|Contact: Olivier CHINOT, PU-PH||491385545 ext +firstname.lastname@example.org|
|Assistance Publique Hôpitaux de Marseille||Recruiting|
|Marseille, France, 13354|
|Contact: Thomas GRAILLON, PH 491385545 ext +33 email@example.com|
|Contact: Olivier CHINOT, PU-PH 491385545 ext +33 firstname.lastname@example.org|
|Principal Investigator: Thomas GRAILLON, PH|
|Study Director:||Jean-Oliver ARNAUD, Director||Assistance Publique Hôpitaux de Marseille|
|Responsible Party:||Assistance Publique Hopitaux De Marseille|
|Other Study ID Numbers:||
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|
|Studies a U.S. FDA-regulated Drug Product:||No|
|Studies a U.S. FDA-regulated Device Product:||No|
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Neoplasms, Vascular Tissue
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Nervous System Diseases
Protein Kinase Inhibitors
Molecular Mechanisms of Pharmacological Action