Cancer research communications · 2022
Phase I Study of High-Dose L-methylfolate in Combination with Temozolomide and Bevacizumab in Recurrent IDH wild-type High-Grade Glioma.
Клиническое исследование I фазыСтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаПоддержка правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Salas Lucas A, Stewart Thomas G, Mobley Bret C, Peng Chengwei, Liu Jing, Loganathan Sudan N, Wang Jialiang, Ma Yanjun, Berger Mitchell S, Absher Devin, Hu Yang, Moots Paul L, Christensen Brock C, Clark Stephen W
Аннотация
PURPOSE: IDH mutations in low-grade gliomas (LGGs) results in improved survival and DNA hypermethylation compared to IDH wild-type LGGs. IDH-mutant LGGs become hypomethylated during progression. It's uncertain if methylation changes occur during IDH wild-type GBM progression and if the methylome can be reprogrammed. This phase I study evaluated the safety, tolerability, efficacy and methylome changes after L-methylfolate (LMF) treatment, in combination with temozolomide and bevacizumab in patients with recurrent high-grade glioma.
PATIENTS AND METHODS: Fourteen patients total, 13 with GBM, one with anaplastic astrocytoma, all IDH wild-type were enrolled in the study. All patients received LMF at either 15, 30, 60, or 90 mg daily plus temozolomide (75mg/m2 5 days per month) and bevacizumab (10mg/kg every two weeks).
RESULTS: No MTD was identified. LMF treated had mOS of 9.5 months (95% CI, 9.1-35.4) comparable to bevacizumab historical control 8.6 months (95% CI, 6.8-10.8). Six patients treated with LMF survived more than 650 days. Across all treatment doses the most adverse events were diarrhea (7%, 1 patient, grade 2), reflux (7%, 1 patient, grade 2), and dysgeusia (7%, 1 patient, grade 2). In the six brains donated at death, there was a 25% increase in DNA methylated CpGs compared to the paired initial tumor.
CONCLUSIONS: LMF in combination with temozolomide and bevacizumab was well tolerated in patients with recurrent IDH wild-type high-grade glioma. This small study did not establish a superior efficacy with addition of LMF compared to standard bevacizumab therapy, however, this study did show methylome reprogramming in high-grade glioma.
PATIENTS AND METHODS: Fourteen patients total, 13 with GBM, one with anaplastic astrocytoma, all IDH wild-type were enrolled in the study. All patients received LMF at either 15, 30, 60, or 90 mg daily plus temozolomide (75mg/m2 5 days per month) and bevacizumab (10mg/kg every two weeks).
RESULTS: No MTD was identified. LMF treated had mOS of 9.5 months (95% CI, 9.1-35.4) comparable to bevacizumab historical control 8.6 months (95% CI, 6.8-10.8). Six patients treated with LMF survived more than 650 days. Across all treatment doses the most adverse events were diarrhea (7%, 1 patient, grade 2), reflux (7%, 1 patient, grade 2), and dysgeusia (7%, 1 patient, grade 2). In the six brains donated at death, there was a 25% increase in DNA methylated CpGs compared to the paired initial tumor.
CONCLUSIONS: LMF in combination with temozolomide and bevacizumab was well tolerated in patients with recurrent IDH wild-type high-grade glioma. This small study did not establish a superior efficacy with addition of LMF compared to standard bevacizumab therapy, however, this study did show methylome reprogramming in high-grade glioma.