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

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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346 First in Pediatrics Phase I Study of Crenolanib Besylate (CP-868, 596–26) Administered During and After Radiation Therapy (RT) in Newly-diagnosed Diffuse Intrinsic Pontine Glioma (DIPG) and Recurrent High Grade Glioma, Including DIPG (HGG)

European Journal of Cancer ◽

10.1016/s0959-8049(12)72144-5 ◽

2012 ◽

Vol 48 ◽

pp. 105-106

Author(s):

C. Wetmore ◽

A. Broniscer ◽

K.D. Wright ◽

A. Pai-Panandiker ◽

Z. Patay ◽

...

Keyword(s):

Radiation Therapy ◽

Phase I ◽

Phase I Study ◽

High Grade Glioma ◽

Diffuse Intrinsic Pontine Glioma ◽

High Grade ◽

Newly Diagnosed ◽

Pontine Glioma

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PDCT-10. FIRST IN PEDIATRICS PHASE I STUDY OF CRENOLANIB BESYLATE (CP-868,596-26) ADMINISTERED DURING AND AFTER RADIATION THERAPY (RT) IN NEWLY-DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND RECURRENT HIGH GRADE GLIOMA (HGG)

Neuro-Oncology ◽

10.1093/neuonc/now212.614 ◽

2016 ◽

Vol 18 (suppl_6) ◽

pp. vi147-vi148 ◽

Cited By ~ 2

Author(s):

Cynthia Wetmore ◽

David Turner ◽

Larry Kun ◽

Arzu Onar-Thomas ◽

Jie Huang ◽

...

Keyword(s):

Radiation Therapy ◽

Phase I ◽

Phase I Study ◽

High Grade Glioma ◽

Diffuse Intrinsic Pontine Glioma ◽

High Grade ◽

Newly Diagnosed ◽

Pontine Glioma

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EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)

Neuro-Oncology ◽

10.1093/neuonc/noaa222.141 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii307-iii307

Author(s):

Mariko DeWire ◽

James Leach ◽

Christine Fuller ◽

Peter de Blank ◽

Trent Hummel ◽

...

Keyword(s):

Phase I ◽

Phase I Study ◽

Single Agent ◽

Maximum Tolerated Dose ◽

Pharmacokinetic Studies ◽

High Grade ◽

Newly Diagnosed ◽

High Grade Gliomas ◽

Grade 3 ◽

Expansion Cohort

Abstract Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.

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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

Neuro-Oncology ◽

10.1093/neuonc/noz175.101 ◽

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.14_suppl.1577 ◽

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

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

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.15_suppl.tps2081 ◽

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

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

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.2543 ◽

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]

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