A phase I study of oral vitamin D3 supplementation in boys with X-linked adrenoleukodystrophy

Objective: Vitamin D status has been linked to risk of inflammatory brain lesions. We sought to assess the safety and pharmacokinetics of oral vitamin D dosing regimens in boys with X-linked adrenoleukodystrophy (ALD). Methods: In this open-label, multi-center, phase I study, we enrolled 21 ALD males without brain lesions, aged 1.5 to 25 years to oral vitamin D supplementation for 12 months. Our primary outcome was attainment of plasma 25-hydroxyvitamin D levels in target range (40-80ng/ml) at 6 and 12 months. Secondary outcomes included safety and glutathione levels in brain and blood. Participants were initially assigned to a fixed dosing regimen starting at 2,000 IU daily, regardless of weight. Following a mid-study safety assessment, we modified the dosing regimen so all subsequent participants were assigned to a weight-stratified dosing regimen starting as low as 1,000 IU daily. Results: Between October 2016 and June 2019, we recruited 21 participants (n=12 fixed dose; n=9 weight-stratified) with a median age and weight of 6.7 years and 20 kilograms. Most participants achieved target plasma vitamin D levels at 6 and 12 months regardless of dosing regimen. In the fixed dose regimen, 6 of 12 participants had asymptomatic elevation in urine calcium:creatinine or plasma 25-hydroxyvitamin D; no laboratory deviations occurred with the weight-stratified regimen. Glutathione levels increased between baseline and 12 months in the brain but not in the blood. Conclusions: Our weight-stratified vitamin D dosing regimen was well-tolerated and achieved target 25-hydroxyvitamin D levels in most participants. Brain glutathione levels increased over the 12-month trial period. Classification of Evidence: This study provides Class II evidence that a weight-stratified dosing regimen of vitamin D supplementation is safe, well-tolerated, and effective at achieving moderately high vitamin D levels in boys with ALD.

Phase I Study of High-Dose l-Methylfolate in Combination with Temozolomide and Bevacizumab in Recurrent IDH Wild-Type High-Grade Glioma

Isocitrate dehydrogenase (IDH) mutations in low-grade gliomas (LGG) result in improved survival and DNA hypermethylation compared with IDH wild-type LGGs. IDH-mutant LGGs become hypomethylated during progression. It is uncertain whether methylation changes occur during IDH wild-type GBM progression and whether 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. 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 (75 mg/m2 5 days per month) and bevacizumab (10 mg/kg every two weeks).No MTD was identified. LMF-treated patients had median overall survival of 9.5 months [95% confidence interval (CI), 9.1–35.4] comparable with 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 with the paired initial tumor. 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 with standard bevacizumab therapy; however, this study did show methylome reprogramming in high-grade glioma. Significance: Glioblastoma (GBM) is a primary brain tumor with a poor prognosis. Therapies to date have failed to improve survival. LGGs, with IDH mutations, have increased global DNA methylation and increased survival compared with GBMs. GBMs lack this mutation and have less DNA methylation. Here we show that the DNA methylome can be modified in GBM with LMF. Such treatment might be useful in methylome priming prior to immunotherapy.