Phase I and Pharmacokinetic Studies of Erlotinib Administered Concurrently with Radiotherapy for Children, Adolescents, and Young Adults with 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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Prospective evaluation of local control and late effects of conformal radiation therapy in children, adolescents, and young adults with high-grade glioma

Neuro-Oncology ◽

10.1093/neuonc/nou101 ◽

2014 ◽

Vol 16 (12) ◽

pp. 1652-1660 ◽

Cited By ~ 16

Author(s):

Tamara Z. Vern-Gross ◽

Jane E. Schreiber ◽

Alberto Broniscer ◽

Shengjie Wu ◽

Xiaoping Xiong ◽

...

Keyword(s):

Young Adults ◽

Radiation Therapy ◽

Local Control ◽

Late Effects ◽

High Grade Glioma ◽

Adolescents And Young Adults ◽

High Grade ◽

Prospective Evaluation ◽

Conformal Radiation Therapy

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Pseudoprogression in children, adolescents and young adults with non-brainstem high grade glioma and diffuse intrinsic pontine glioma

Journal of Neuro-Oncology ◽

10.1007/s11060-016-2151-8 ◽

2016 ◽

Vol 129 (1) ◽

pp. 109-121 ◽

Cited By ~ 15

Author(s):

Fernando Carceller ◽

Lucy A. Fowkes ◽

Komel Khabra ◽

Lucas Moreno ◽

Frank Saran ◽

...

Keyword(s):

Young Adults ◽

High Grade Glioma ◽

Diffuse Intrinsic Pontine Glioma ◽

Adolescents And Young Adults ◽

High Grade ◽

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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CTNI-41. INITIAL RESULTS OF A PHASE I WINDOW OF OPPORTUNITY TRIAL EVALUATING A FIRST-IN-CLASS CD29 INHIBITOR, OS2966, IN RECURRENT HIGH-GRADE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.266 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi69-vi69

Author(s):

James Liu ◽

Chibueze D Nwagwu ◽

Amanda V Immidisetti ◽

Gabriela Bukanowska ◽

Anne-Marie Carbonell ◽

...

Keyword(s):

Adverse Events ◽

Phase I ◽

Tumor Resection ◽

High Grade Glioma ◽

Underlying Disease ◽

Tissue Level ◽

High Grade ◽

Convection Enhanced Delivery ◽

Tumor Biopsy ◽

Safety Issues

Abstract BACKGROUND OS2966 is a first-in-class, humanized and deimmunized monoclonal antibody which antagonizes CD29/β1integrin, a mechanosignaling receptor prominently upregulated in glioblastoma. Preclinical studies in mice and non-human primates have demonstrated safety and encouraging efficacy. A two-part, ascending concentration, phase I clinical trial was therefore initiated to evaluate the safety and feasibility of delivering OS2966 directly to the site of disease via convection-enhanced delivery (CED) in recurrent high-grade glioma patients. METHODS This study has a 2-part design: In part 1, patients undergo stereotactic tumor biopsy followed by placement of a multiport CED catheter for delivery of OS2966 to the bulk contrast enhancing tumor. Subsequently, patients undergo a clinically-indicated tumor resection followed by placement of two CED catheters and delivery of OS2966 to the surrounding tumor-infiltrated brain. A unique concentration-based accelerated titration design is utilized for dose escalation. Given availability of pre and post infusion samples, pharmacodynamic data will be analyzed to explore mechanism of action of OS2966. RESULTS Two subjects have been treated at two corresponding dose levels (0.2mg/mL and 0.4 mg/mL). No dose-limiting toxicity or unexpected safety issues have been identified. To date, reported adverse events were mild (i.e., grade 1) and consistent with underlying disease and surgical procedures. No adverse events were attributed to OS2966 or CED catheter placement. Further, no clinically significant changes from baseline neurological exam have been noted for either patient through initial follow-up. Maximal tumor coverage and concomitant gross total resection were achieved for both patients. Tumor volume measured 1.63 cm3 and 16 cm3 for Patient 1 and 2 respectively with an intratumoral Vd/Vi ratio of 1.3. and 0.94. Pharmacodynamic analysis via tissue-level biomarkers is ongoing and will be presented. CONCLUSION Initial data demonstrates the safety and feasibility of direct intracranial delivery of OS2966.

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Phase I and Biomarker Study of Plerixafor and Bevacizumab in Recurrent High-Grade Glioma

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-18-1025 ◽

2018 ◽

Vol 24 (19) ◽

pp. 4643-4649 ◽

Cited By ~ 9

Author(s):

Eudocia Q. Lee ◽

Dan G. Duda ◽

Alona Muzikansky ◽

Elizabeth R. Gerstner ◽

John G. Kuhn ◽

...

Keyword(s):

Phase I ◽

High Grade Glioma ◽

High Grade

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EPCO-07. HYBRID NEURO-GLIAL CELLULAR ARCHITECTURE IN HIGH-GRADE GLIOMA DRIVEN BY H3-G34R MUTATION

Neuro-Oncology ◽

10.1093/neuonc/noab196.006 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi2-vi2

Author(s):

Julie Laffy ◽

Masashi Nomura ◽

Chen He ◽

Lillian Bussema ◽

Michal Slyper ◽

...

Keyword(s):

Young Adults ◽

Rna Sequencing ◽

Developmental Trajectories ◽

High Grade Glioma ◽

Cerebral Hemispheres ◽

High Grade ◽

Malignant Cells ◽

Aberrant Expression ◽

Cellular Architecture ◽

Single Nucleus

Abstract High-grade gliomas (HGG) with histone H3.3 G34R mutation are rare intractable tumours in the cerebral hemispheres that preferentially affect adolescents and young adults, but have unknown mechanisms of neuroanatomical specificity and tumourigenesis. Here, we performed single-nucleus RNA-sequencing of twenty patient samples, encompassing twelve tumours with G34R mutation and eight H3.3 wildtype HGGs, age- and location-matched. Both classes of HGG were heterogeneous, with malignant cells in multiple states, recapitulating neural and glial developmental trajectories. G34R HGG is distinguished by lack of malignant cells in the oligodendroglial lineage, and aberrant expression of neuronal programs superimposed over cellular states, resulting in hybrid glio-neuronal malignant programs. Singe-cell barcoding supports plasticity between cellular states in HGG with multiple possible transitions. CRISPR-correction of G34R in HGG models followed by scRNA-seq supports that the G34R mutation directly drives these aberrant programs. Our study provides a framework for studying the origin and tumourigenesis of paediatric gliomas.

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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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