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Phase I Study of High-Dose L-methylfolate in Combination with Temozolomide and Bevacizumab in Recurrent IDH wild-type High-Grade Glioma.

  • 2022-01-05
  • Cancer research communications 2(1)
    • Lucas A Salas
    • Thomas G Stewart
    • Bret C Mobley
    • Chengwei Peng
    • Jing Liu
    • Sudan N Loganathan
    • Jialiang Wang
    • Yanjun Ma
    • Mitchell S Berger
    • Devin Absher
    • Yang Hu
    • Paul L Moots
    • Brock C Christensen
    • Stephen W Clark

Study Design

Type
Clinical Trial
Population
Fourteen patients total, 13 with GBM, one with anaplastic astrocytoma, all IDH wild-type
Methods
Phase I 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)
Blinding
Open-label
Funding
Unclear

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.

Research Insights

  • L-Methylfolate→Improved Overall Survival

    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).

    Effect
    Neutral
    Effect size
    Small
    Dose
    15, 30, 60, or 90 mg daily

Adverse Events Reported

  • L-Methylfolate→Overall tolerability

    No MTD was identified. LMF in combination with temozolomide and bevacizumab was well tolerated in patients with recurrent IDH wild-type high-grade glioma.

    Finding
    Reported
  • L-Methylfolate→diarrhea

    Across all treatment doses the most adverse events were diarrhea (7%, 1 patient, grade 2)

    Finding
    Reported
    Grade
    moderate
  • L-Methylfolate→dysgeusia

    Across all treatment doses the most adverse events were ... dysgeusia (7%, 1 patient, grade 2)

    Finding
    Reported
    Grade
    moderate
  • L-Methylfolate→reflux

    Across all treatment doses the most adverse events were ... reflux (7%, 1 patient, grade 2)

    Finding
    Reported
    Grade
    moderate
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