Ivy Brain Tumor Center To Present 11 Abstracts at the 2021 SNO Annual Meeting

• November 18, 2021
• Ivy Center
• Posted in Clinical Trials

SNO Meeting 2021 

At the 26th Annual Meeting of the Society for Neuro-Oncology (SNO), the Ivy Brain Tumor Center’s team of brain tumor specialists and scientists will present 11 abstracts based on our preclinical and clinical research findings. The abstracts are published in the journal of Neuro-Oncology.

Founded in 2018 and located at Barrow Neurological Institute, the Ivy Center’s research program is singularly focused on discovering new therapies for brain tumor patients through a broad portfolio of pharmacodynamic- and pharmacokinetic-driven clinical trials, combining industry-partnered drug development with the nation’s largest operative brain tumor volume. 

With seven active clinical trials and more slated to open by the end of the year, we operate the largest Phase 0 clinical trials program in the world for brain cancer. Our team is committed to accelerating drug discovery and precision medicine in neuro-oncology in an effort to identify the most promising first-in-class therapies for brain tumor patients. 

To learn more about the research that will be presented at SNO, check out the summary below. 

Ivy Brain Tumor Center’s Abstract Session

Session Title: CTNI-48 – A Phase 0 ‘Trigger’ Trial of CDK4/6 plus ERK1/2 Inhibitors in Recurrent Glioblastoma 

• Abstract Session: Clinical Trials II
  • Saturday, November 20, 2021, 11:15-11:25 AM EST, Ballroom C 
    
• Abstract Session Presenter
  • Nader Sanai, MD, Chief Scientific Officer and Director, Ivy Brain Tumor Center at Barrow Neurological Institute
    
• Background 
  • This dual-drug Phase 0 study (NCT04391595) evaluates the tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of abemaciclib, a selective CDK4/6-inhibitor, plus LY3214996, a selective ERK1/2 inhibitor, in recurrent GBM patients. 
    
• Conclusion
  • Abemaciclib and LY3214996 achieve pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue and are associated with suppression of the RB pathway and tumor proliferation. The Optimal Time Interval (OTI) for tissue sampling was 3-5 hours after the final drug dose. Based on this interim analysis, the trial will accrue an additional 25 patients at this OTI.

To review the full abstract, click here.  For more information, visit NCT04391595. 

 Ivy Brain Tumor Center’s SNO Posters

1. Poster Title: CTNI-23 – A First-in-Human Phase 0/1 Clinical Trial of 5-Aminolevulinic Acid Sonodynamic Therapy in Recurrent Glioblastoma

• Poster Presenter
  • Shwetal Mehta, PhD, Chief Operating Officer and Deputy Director, Ivy Brain Tumor Center at Barrow Neurological Institute

• Background
  • 5-aminoleveulinic acid sonodynamic therapy (5-ALA SDT) is a drug-device strategy that exploits the metabolic liabilities of cancer.  Following systemic administration of 5-ALA, aberrant tumor metabolism leads to accumulation of protoporphyrin-IX (PpIX).  Activation of PpIX by non-invasive, non-ablative magnetic resonance-guided focused ultrasound (MRgFUS) induces reactive oxygen species and tumor cell death. This first-in-human Phase 0/1 study investigates the feasibility, safety, and biological effects of 5-ALA SDT in recurrent glioblastoma (GBM) patients.

• Conclusion 
  • This first-in-human experience with a new therapeutic modality for recurrent glioblastoma patients demonstrates that 5-ALA SDT is safe at 200J. Sonodynamic therapy leads to targeted oxidative stress and tumor cell death in human glioblastoma tissue.

To review the full abstract, click here. For more information, visit NCT04559685.  

2. Poster Title: CTNI-22 – A Phase 0/1 ‘Trigger’ Trial of Ribociclib Plus Everolimus in Recurrent High-Grade Glioma

• Poster Presenter
  • An-Chi Tien, PhD, Pharmacodynamics Core Leader, Ivy Brain Tumor Center at Barrow Neurological Institute

• Background
  • The RB-CDK4/6 and mTOR signaling pathways are deregulated in high-grade glioma (HGG) and mTOR activation is a potential mechanism of resistance to CDK4/6 inhibition. This study evaluates the tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of combined CDK4/6 and mTOR inhibition in recurrent HGG patients.

• Conclusion
  • In adult HGG, ribociclib achieves pharmacologically-relevant concentrations in Gd-nonenhancing tumor, consistent with the observed tumor PD effects.  Everolimus exhibits very limited penetration into human glioma tissue. Our study supports further development of ribociclib, but not everolimus, for the treatment of glioma patients.

To review the full abstract, click here. For more information, visit NCT03834740. 

3. Poster Title: DDRE-12 – Determination of total and unbound levels of a potent inhibitor of fibroblast growth factor receptor, infigratinib, in human plasma, cerebrospinal fluid and brain tumor by a validated LC-MS/MS assay

• Poster Presenter
  • Tigran Margaryan, PhD, Postdoctoral Fellow, Ivy Brain Tumor Center at Barrow Neurological Institute
• Background 
  • Infigratinib is an orally available potent inhibitor of fibroblast growth factor receptor (FGFR) under investigation in a Phase 0 clinical trial for recurrent high-grade gliomas harboring oncogenic FGFR mutation or translocation (NCT04424966). Here, we report on our development and validation of an LC-MS/MS method for determination of total and unbound levels of infigratinib in human plasma, cerebrospinal fluid (CSF) and glioblastoma tissue. 
• Conclusion 
  • A sensitive and rapid bioanalytical method is successfully developed and validated to quantify total and unbound infigratinib levels in human plasma, CSF and glioblastoma tissue. The method is presently employed to evaluate plasma pharmacokinetics and CNS penetration of infigratinib in recurrent glioblastoma patients in an ongoing Phase 0 clinical trial.

To review the full abstract, click here. For more information, visit NCT04424966. 

4. Poster Title: STEM-19 – Non-redundant, Isoform-Specific Roles of HDAC1 in the Regulation of the Glioma Stem Cell Phenotype

• Poster Presenter
  • Costanza Lo Cascio, B.Sc., PhD Candidate, Ivy Brain Tumor Center at Barrow Neurological Institute

• Background 
  • Glioblastoma (GBM) is characterized by an aberrant yet druggable epigenetic landscape. One major family of epigenetic regulators, the Histone Deacetylases (HDACs), are considered promising therapeutic targets for GBM due to Glioblastoma (GBM) is characterized by an aberrant yet druggable epigenetic landscape. One major family of epigenetic regulators, the Histone Deacetylases (HDACs), are considered promising therapeutic targets for GBM due to their repressive influences on transcription. Although HDACs share redundant functions and common substrates, the unique isoform-specific roles of different HDACs in GBM remain unclear. There is a temporal and cell-type specific requirement of HDAC1 and 2 during normal brain development, with HDAC2 being indispensable in neural stem cells. Here, we specifically investigated the functional importance of HDAC1 in glioma stem cells, an HDAC isoform whose expression increases with brain tumor grade and is correlated with decreased survival.

• Conclusion
  • Our findings reveal an essential non-redundant role of HDAC1 in GSCs, in contrast to its dispensability in normal neural stem cells.Knockdown of HDAC1 alone prolongS survival of  PDX and mouse models of human glioma, and the resulting tumors exhibit a more invasive growth pattern.We identified STAT3 signaling axis as a promising and druggable compensatory pathway that is upregulated after HDAC1 loss in p53-wild type GSCs.

To review the full abstract, click here. 

5. Poster Title: CTNI-20 – Feasibility of Single-Pass Stereotactic Needle Biopsy in Recurrent Glioblastoma Patients to Support CLIA-Certified Tumor Pharmacodynamics for a Phase 0/2 Clinical Trial

• Poster Presenter
  • Anita DeSantis, B.S., Research Tech, Ivy Brain Tumor Center at Barrow Neurological Institute

• Background
  • In neuro-oncology clinical trials, pharmacodynamic (PD) analysis of tumor tissue before and after experimental therapy is challenging. Today, Phase 0 studies in brain tumor patients typically employ archival tissue from a prior resection as the baseline PD comparator. However, the time-interval between tissue acquisitions can be months to years and often includes confounding exposure to other therapies. Here, we demonstrate the feasibility of a pre-treatment, single-pass stereotactic needle biopsy to support CLIA-certified genetic screening and tumor PD analysis in a Phase 0/2 clinical trial.

• Conclusion
  • Single-pass stereotactic needle biopsy is a feasible and safe strategy to collect pre-treatment tissue in support of a Phase 0 clinical trial, enabling CLIA-certified genetic analysis for trial screening and tumor PD analysis.

To review the full abstract, click here. 

6. Poster Title: EXTH-09 – Tumor Pharmacokinetics, Pharmacodynamics and Radiation Sensitization in Patient-Derived Xenograft Models of Glioblastoma Treated with the Aurora Kinase A inhibitor LY3295668

• Poster Presenter
  • Sarah Himes, B.S., Research Technician, Ivy Brain Tumor Center at Barrow Neurological Institute
    
• Background
  • Cell-cycle deregulation is at the crux of all malignancies, including glioblastoma (GBM). Aurora Kinase A (AURKA) plays a central role in G2/M transition and faithful chromosome segregation. In this study, we evaluated the pharmacokinetics, pharmacodynamics, and radiation sensitization properties of LY3295668, a highly specific AURKA inhibitor, in orthotopic patient-derived xenograft (PDX) models of GBM. 
    
• Conclusion 
  • Combination of LY3295668 with radiotherapy prolonged survival compared to either therapy alone in orthotopic GBM PDX models. LY3295668 is well tolerated, achieves pharmacologically-relevant unbound concentrations in GBM PDX models, and is associated with significant target modulation. Preclinical combination of LY3295668 with radiation therapy leads to synergistic effects and supports future clinical study of this multimodal strategy in glioblastoma patients.

To review the full abstract, click here. 

7. Poster Title: EXTH-24 – Tumor Pharmacokinetics, Pharmacodynamics and Radiation Sensitization in Patient-Derived Xenograft Models of Glioblastoma Treated with the Second-Generation HDAC inhibitor, Quisinostat 

• Poster Presenter
  • James McNamara, B.S., Research Technician, Ivy Brain Tumor Center at Barrow Neurological Institute

• Background 
  • Class I Histone deacetylases (HDACs) are highly expressed in glioblastoma (GBM) and are considered promising therapeutic targets for cancer treatment. Quisinostat is a class I HDAC inhibitor with high specificity for HDAC1 and 2. In this study, we evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and radiation sensitization properties of quisinostat in orthotopic and flank human glioma models of GBM. 

• Conclusion
  • Quisinostat treatment inhibits cellular growth, with an IC50 value between 30-70 nM, and potentiates the effects of radiation in vitro. Upon Quisinostat treatment, cells decrease proliferation and show lower expression of the stemness marker Olig2 while upregulating the cell cycle arrest protein p21. Peak mouse plasma concentration, 752.3 nM, is achieved 0.5 hours after intraperitoneal treatment. Quisinostat inhibits U87LN tumor growth in vivo, and there is sufficient drug levels in the tumor to induce increase histone H3 acetylation.

To review the full abstract, click here. 

8. Poster Title: BIOM-13 – Development and validation of an LC-MS/MS assay to measure glutathione, glutathione disulfide, cysteine, and cystine in human brain and human glioblastoma 

• Poster Presenter
  • Artak Tovmasyan, PhD, Pharmacokinetics Core Leader, Ivy Brain Tumor Center, Barrow Neurological Institute
    
• Background
  • Oxidative stress is implicated in many pathological conditions. Herein, we report on our development and validation of a sensitive and rapid LC-MS/MS method for the determination of oxidative stress biomarkers glutathione (GSH), glutathione disulfide (GSSG), cysteine (Cys) and cystine (CySS) in human brain and glioblastoma tissue. 

• Conclusion
  • A bioanalytical method to quantify GSH, GSSG, Cys, and CySS is successfully developed and validated. The method is currently applied to measure thiols and related disulfides in human glioblastoma tissue undergoing 5-aminolevulinic acid sonodynamic therapy.

To review the full abstract, click here. For more information, visit NCT04559685.

9. Poster Title: DDRE-08 – A bioanalytical LC-MS/MS assay to quantify total and unbound LY3214996, abemaciclib and its active metabolites in human plasma, cerebrospinal fluid and human glioblastoma

• Poster Presenter
  • Artak Tovmasyan, PhD, Pharmacokinetics Core Leader, Ivy Brain Tumor Center, Barrow Neurological Institute
    
• Background 
  • Here, we report on our development and validation of a sensitive and rapid LC-MS/MS method for the determination of total and unbound concentrations of ERK inhibitor LY3214996, CDK4/6 inhibitor abemaciclib and its M2 and M20 active metabolites in human plasma, cerebrospinal fluid and human glioblastoma tissue. 
    
• Conclusion
  • A bioanalytical method to quantify LY3214996, abemaciclib and its M2 and M20 metabolites is successfully developed and validated. The method is currently applied to evaluate plasma pharmacokinetics and CNS penetration of LY3214996 and abemaciclib in recurrent glioblastoma patients in an ongoing Phase 0 clinical trial (NCT04391595).

To review the full abstract, click here. For more information, visit NCT04391595.

10. Poster TItle: DDRE-23 – Preclinical evaluation of brain penetration properties of new first-in-class lysine-specific demethylase 1 (LSD1) inhibitor, SP-2577 

• Poster Presenter
  • Artak Tovmasyan, PhD, Pharmacokinetics Core Leader,  Ivy Brain Tumor Center, Barrow Neurological Institute
    
• Background 
  • Lysine specific demethylase 1 (LSD1) is a histone demethylase implicated in the maintenance of pluripotency and proliferation gene programs that give rise to a number of cancers. SP-2577 is a first-in-class selective and reversible inhibitor of LSD1. Here, we evaluated the ability of SP-2577 to cross blood-brain barrier in mouse brain. 
    
• Conclusion 
  • SP-2577 is well tolerated in mice and achieves reasonable total drug levels in mouse brain, yet is highly-bound to plasma proteins and brain components. Taken together, these data indicate that SP-2577 cannot reach pharmacologically-relevant drug concentrations across the mouse blood-brain barrier. 

To review the full abstract, click here.