Cancer · 2018
Phase 1 lead-in to a phase 2 factorial study of temozolomide plus memantine, mefloquine, and metformin as postradiation adjuvant therapy for newly diagnosed glioblastoma.
Клиническое исследование I фазыСтатьяНазвание и аннотация: Перевод в очереди
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Maraka Stefania, Groves Morris D, Mammoser Aaron G, Melguizo-Gavilanes Isaac, Conrad Charles A, Tremont-Lukats Ivo W, Loghin Monica E, O'Brien Barbara J, Puduvalli Vinay K, Sulman Erik P, Hess Kenneth R, Aldape Kenneth D, Gilbert Mark R, de Groot John F, Alfred Yung W K, Penas-Prado Marta
Аннотация
BACKGROUND: Repurposed memantine, mefloquine, and metformin have putative anticancer activity. The objective of this phase 1 study was to determine the maximum tolerated doses (MTDs) of combinations of these agents with temozolomide (TMZ).
METHODS: Adults with newly diagnosed glioblastoma who completed chemoradiation were eligible. The patients were assigned to receive doublet, triplet, or quadruplet therapy with TMZ combined with mefloquine, memantine, and/or metformin. Dose-limiting toxicities (DLTs) were determined, using a 3 + 3 study design.
RESULTS: Of 85 enrolled patients, 4 did not complete cycle 1 (the DLT observation period) for nontoxicity reasons, and 81 were evaluable for DLT. The MTDs for doublet therapy were memantine 20 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For triplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For quadruplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 500 mg twice daily. DLTs included dizziness (memantine) and gastrointestinal effects (metformin). Lymphopenia was the most common adverse event (66%). From study entry, the median survival was 21 months, and the 2-year survival rate was 43%.
CONCLUSIONS: Memantine, mefloquine, and metformin can be combined safely with TMZ in patients with newly diagnosed glioblastoma.
METHODS: Adults with newly diagnosed glioblastoma who completed chemoradiation were eligible. The patients were assigned to receive doublet, triplet, or quadruplet therapy with TMZ combined with mefloquine, memantine, and/or metformin. Dose-limiting toxicities (DLTs) were determined, using a 3 + 3 study design.
RESULTS: Of 85 enrolled patients, 4 did not complete cycle 1 (the DLT observation period) for nontoxicity reasons, and 81 were evaluable for DLT. The MTDs for doublet therapy were memantine 20 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For triplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For quadruplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 500 mg twice daily. DLTs included dizziness (memantine) and gastrointestinal effects (metformin). Lymphopenia was the most common adverse event (66%). From study entry, the median survival was 21 months, and the 2-year survival rate was 43%.
CONCLUSIONS: Memantine, mefloquine, and metformin can be combined safely with TMZ in patients with newly diagnosed glioblastoma.
Предметные рубрики MeSH
AdultAgedAntineoplastic Combined Chemotherapy ProtocolsBrain NeoplasmsChemotherapy, AdjuvantClinical Trials, Phase II as TopicFemaleGlioblastomaHumansMaleMaximum Tolerated DoseMefloquineMemantineMetforminMiddle AgedProgression-Free SurvivalRadiotherapy, AdjuvantResearch DesignTemozolomideTreatment OutcomeYoung Adult