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

2022 ◽  
Vol 2 (1) ◽  
pp. 1-9
Author(s):  
Lucas A. Salas ◽  
Thomas G. Stewart ◽  
Bret C. Mobley ◽  
Chengwei Peng ◽  
Jing Liu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Phase I ◽  
Phase I Study ◽  
High Grade Glioma ◽  
High Dose ◽  
Low Grade ◽  
High Grade ◽  
Wild Type ◽  
Dna Hypermethylation ◽  
Idh Mutations

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.

scholarly journals ACTR-59. A PHASE 1 STUDY OF BPM31510 PLUS VITAMIN K IN SUBJECTS WITH HIGH-GRADE GLIOMA THAT HAS RECURRED ON A BEVACIZUMAB-CONTAINING REGIMEN

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi27-vi27
Author(s):  
Lawrence Recht ◽  
Reena Thomas ◽  
Sophie Bertrand ◽  
Priya Yerballa ◽  
Gordon Li ◽  
...  
Keyword(s):  
Phase I ◽  
Vitamin K ◽  
Phase I Study ◽  
Phase 1 ◽  
High Grade Glioma ◽  
High Grade ◽  
Open Label ◽  
Open Label Phase ◽  
Grade 3

Abstract BACKGROUND High-grade gliomas (HGG) are characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an ubidecarenone (coenzyme Q10) containing lipid nanodispersion, causes a switch in cancer energy sourcing from glycolysis towards mitochondrial oxidative phosphorylation in vitro, reversing the Warburg effect and suggesting potential as an anti-tumor agent. The current study is a phase I study of BPM31510 + vitamin K in GB with tumor growth after bevacizumab (BEV). METHODS This is an open-label phase I study of BPM31510 continuous infusion with weekly vitamin K (10mg IM) in HGG patients using an mTPI design, starting at 110mg/kg, allowing for a single dose de-escalation and 2 dose-escalations. Patients had received first-line ChemoRadiation and were in recurrence following a BEV containing regimen. RESULTS 9 eligible and evaluable patients completed the 28 day DLT period. 8 patients had primary GB, 1 had anaplastic astrocytoma with confirmed pathologic transformation to GB. Median age was 55 years (27–67) and median KPS 70 (60–90) at enrollment. 4 patients were treated at the highest dose 171mg/kg, where there was a single DLT: Grade 3 AST & ALT. The most common grade 1–2 AEs possibly, probably or definitely related to drug were elevated AST, rash, and fatigue, each occurring in 3 patients. Median OS for 9 eligible/evaluable patients was 128 days (95% CI: 48–209) while PFS was 34 days (CI of mean 8.9). 3 patients are currently alive; 2 patients have survived >1 year. PK/PD data are being processed and will be presented. CONCLUSION This study confirms that BPM 31510 + vitamin K is safe and feasible in treatment-refractory HGG patients. Though this study demonstrates safety at 171mg/kg, the proposed dose for future studies in GB, based on additional pre-clinical and non-GB clinical data is 88mg/kg.

Temozolomide (TMZ) and lomustine (CCNU) in high grade glioma (HGG) patients: Phase I study

2004 ◽  
Vol 22 (14_suppl) ◽  
pp. 1577-1577
Author(s):  
S. Tafuto ◽  
R. Guarrasi ◽  
A. Tortoriello ◽  
F. Buzzi ◽  
P. Muto ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
High Grade Glioma ◽  
High Grade

Phase I study of aflibercept (VEGF Trap) and temozolomide in newly diagnosed, high-grade glioma.

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 2043-2043
Author(s):  
J. F. De Groot ◽  
T. Cloughesy ◽  
F. S. Lieberman ◽  
S. M. Chang ◽  
A. M. P. Omuro ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
High Grade Glioma ◽  
High Grade ◽  
Newly Diagnosed ◽  
Vegf Trap

A phase I study of convection-enhanced delivery of nanoliposomal irinotecan using real-time imaging in patients with recurrent high grade glioma.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. TPS2081-TPS2081
Author(s):  
Nicholas A. Butowski ◽  
Seunggu Han ◽  
Jennie Webster Taylor ◽  
Manish K. Aghi ◽  
Michael Prados ◽  
...  
Keyword(s):  
Phase I ◽  
Real Time ◽  
Phase I Study ◽  
High Grade Glioma ◽  
High Grade ◽  
Convection Enhanced Delivery ◽  
Real Time Imaging ◽  
Nanoliposomal Irinotecan

Phase I study of BPM31510 and vitamin K in patients with high grade glioma recurrent after a bevacizumab-containing regimen.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2543-2543
Author(s):  
Seema Nagpal ◽  
Reena Parada Thomas ◽  
Sophie Bertrand ◽  
Hari Priya Yerraballa ◽  
Michael Iv ◽  
...  
Keyword(s):  
Phase I ◽  
Vitamin K ◽  
Phase I Study ◽  
High Grade Glioma ◽  
Clinical Development ◽  
High Grade ◽  
Open Label ◽  
Tumor Bed ◽  
Mitochondrial Superoxide ◽  
Open Label Phase

2543 Background: BPM31510 is an ubidecarenone-lipid conjugate nanodispersion in clinical development for advanced malignancies, including high grade glioma (HGG). BPM31510’s anti-cancer effect is mediated by induction of mitochondrial superoxide and activation of cell death in glioblastoma models. Herein, we present preliminary pharmaco-kinetic and dynamic data, and survival from a phase I study of BPM31510 + Vitamin K in HGG with progression after bevacizumab (BEV). Methods: This was an open-label phase I study of BPM31510 continuous infusion with Vitamin K (10mg IM qweek) using a mTPI design, starting at 110mg/kg 2X/week, allowing 2 dose escalations & 1 de-escalation. Patients had received ChemoRT and were in recurrence after BEV. Results: Of 12 patients treated with BPM31510, 9 completed the 28-day DLT period. 2 patients came off study for progressive disease; 1 patient after asymptomatic hemorrhage into tumor bed (G1). 10 patients had primary GB, 2 had AA. Median age was 54.5yo (27-67) and KPS 70 (60-90). On Day 1 of BPM31510, a dose dependent increase in Cmax was observed; Tmax values were similar for all doses. AUC was linear with dose escalation. For all doses, Day 4 Cmax values were higher compared to Day 1. In contrast there was variable decrease in Tmax (table). Of evaluable patients, 4 patients received the highest dose 171mg/kg, where a single patient experienced DLT: G3 AST & ALT. The most common grade 1/2 AEs were elevated AST, rash, and fatigue, each occurring in 4 patients. The mOS for 9 eligible/evaluable patients was 128 days (95% CI: 48-209) while PFS was 34 days (95% CI of mean 8.9). Two patients are currently alive >12 months. Conclusions: BPM31510 + vitamin K demonstrated a safe profile to maximum dose of 171mg/kg twice/week with potential therapeutic utility in treatment-refractory HGG patients. Multi-omic molecular profiles characterizing AE and response to be reported from the study will be investigated for next phase of clinical development. Clinical trial information: NCT03020602 . [Table: see text]

scholarly journals A dose escalating phase I study of GLPG0187, a broad spectrum integrin receptor antagonist, in adult patients with progressive high-grade glioma and other advanced solid malignancies

2016 ◽  
Vol 34 (2) ◽  
pp. 184-192 ◽  
Author(s):  
Geert A. Cirkel ◽  
Bojana Milojkovic Kerklaan ◽  
Frédéric Vanhoutte ◽  
Annegret Van der Aa ◽  
Giocondo Lorenzon ◽  
...  
Keyword(s):  
Phase I ◽  
Receptor Antagonist ◽  
Broad Spectrum ◽  
Phase I Study ◽  
High Grade Glioma ◽  
Adult Patients ◽  
High Grade ◽  
Integrin Receptor ◽  
Solid Malignancies ◽  
Dose Escalating

Phase I study of non-pegylated liposomal doxorubicin in children with recurrent/refractory high-grade glioma

2015 ◽  
Vol 76 (2) ◽  
pp. 425-432 ◽  
Author(s):  
Pascal Chastagner ◽  
Bénédicte Devictor ◽  
Birgit Geoerger ◽  
Isabelle Aerts ◽  
Pierre Leblond ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
High Grade Glioma ◽  
High Grade

Phase I study of erlotinib administered concurrently with and after irradiation (RT) in the treatment of children, adolescents, and young adults with newly diagnosed intracerebral high-grade glioma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9553-9553
Author(s):  
A. Broniscer ◽  
S. J. Baker ◽  
T. E. Merchant ◽  
F. H. Laningham ◽  
M. Kocak ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
High Grade Glioma ◽  
Maximum Tolerated Dose ◽  
Exclusion Criterion ◽  
Pharmacokinetic Studies ◽  
High Grade ◽  
Newly Diagnosed ◽  
High Grade Gliomas ◽  
Grade 3

9553 Background: High-grade gliomas are uncommon neoplasms in childhood that portend a poor prognosis. Because of the promising activity of erlotinib in adults with high-grade glioma, we conducted this Phase I study to determine the maximum tolerated dose and dose limiting toxicity (DLT) of erlotinib administered concurrently with and after RT. Methods: Patients between 3 and 25 years of age with newly diagnosed high-grade glioma received erlotinib continuously once daily during and after RT for a maximum of 52 weeks. Pharmacokinetic studies of erlotinib and its metabolite OSI-420, and genotyping were performed during course 1 in consenting patients. Use of enzyme-inducing anticonvulsants was an exclusion criterion. Dose escalation followed a typical Phase I design (dosage levels of 70, 90, and 120 mg/m2 per day). The DLT-evaluation period comprised the first 8 weeks of erlotinib. Results: Seventeen patients (median age 10.4 yrs; 10 males) were enrolled. Diagnoses consisted of glioblastoma (n=9), anaplastic astrocytoma (n=4), and other high-grade gliomas (n=4). Two of seven patients experienced reversible grade 3 hypokalemia / hypophosphatemia at the 70 mg/m2 level. Once electrolyte abnormalities were excluded as DLT, only one of seven patients at the 120 mg/m2 level has experienced grade 3 diarrhea so far. Pharmacokinetic studies were obtained in 14/17 patients. At the 70 mg/m2 dosage level, the median (range) erlotinib and OSI-420 Cmax and Tmax were 1,405 ng/ml (937–2,180) and 4.1 hr (2.2–8.2) and 158.5 ng/ml (45–203) and 4.1 hr (2.2–7.9), respectively. Three patients have received erlotinib for more than 1 year with disease stabilization. Six patients have already experienced disease progression. Conclusions: Erlotinib administered concurrently with RT on this schedule has been well tolerated. Preliminary pharmacokinetic results are comparable to those observed in adults. Rather than continue to escalate erlotinib dosages, we plan to complete this study and open a phase II study of erlotinib and RT for this same patient population. No significant financial relationships to disclose.

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