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Figure A3 from Rindopepimut with Bevacizumab for Patients with Relapsed EGFRvIII-Expressing Glioblastoma (ReACT): Results of a Double-Blind Randomized Phase II Trial

File (tmp-LBN-Report_PH-DMPK-UAB-19-001_SRI-42127 _Mouse IP Plasma Brain PK) provides pharmacokinetic data for Fig. S14.

Supplementary materials including tables, figures, and detailed methods.

Web Extra Material - 2 tables and 3 figures

Purpose:Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma.Patients and Methods:In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2.Results:Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control (P = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32–0.88; two-sided log-rank P = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; P = 0.38)], median duration of response [7.8 months (95% CI, 3.5–22.2) vs. 5.6 (95% CI, 3.7–7.4)], and ability to discontinue steroids for ≥6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07–0.45; P < 0.0001).Conclusions:Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM.See related commentary by Wick and Wagener, p. 1535

Purpose Patients with recurrent glioblastoma (rGBM) have a poor prognosis. Epidermal growth factor receptor (EGFR) gene amplification is present in ~ 50% of glioblastomas (GBMs). Depatuxizumab mafodotin (depatux-m), formerly ABT-414, is an antibody–drug conjugate that preferentially binds cells with EGFR amplification, is internalized and releases a potent antimicrotubule agent, monomethyl auristatin F (MMAF). Here we report the safety, pharmacokinetics, and efficacy of depatux-m monotherapy at the recommended Phase 2 dose (RPTD) in patients with EGFR-amplified, rGBM. Methods M12-356 (NCT01800695) is an open-label study with three escalation and expansion cohorts. Sixty-six patients with EGFR-amplified, rGBM were treated with depatux-m monotherapy at 1.25 mg/kg intravenously every 2 weeks. Adults with measurable rGBM, who were bevacizumab-naïve, with EGFR amplification were eligible. Results Among 66 patients, median age was 58 years (range 35–80). All patients were previously treated with radiotherapy/temozolomide. The most common adverse events (AEs) were eye related (91%), including blurred vision (65%), dry eye (29%), keratitis, and photophobia (27% each). Grade 3/4 AEs occurred in 42% of all patients, and ocular Grade 3/4 AEs occurred in 33% of patients overall. One patient (2%) had a Grade 4 ocular AE. Ocular AEs were manageable and usually resolved once treatment with depatux-m ceased. The objective response rate was 6.8%, the 6-month progression-free survival rate was 28.8%, and the 6-month overall survival rate was 72.5%. Conclusion Depatux-m monotherapy displayed frequent but mostly Grade 1/2 ocular toxicities. A PFS6 of 28.8% was observed in this rGBM population, warranting further study. Electronic supplementary material The online version of this article (doi:10.1007/s00280-017-3451-1) contains supplementary material, which is available to authorized users.

Glial activation with the production of pro-inflammatory mediators is a major driver of disease progression in neurological processes ranging from acute traumatic injury to chronic neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. Posttranscriptional regulation is a major gateway for glial activation as many mRNAs encoding pro-inflammatory mediators contain adenine- and uridine-rich elements (ARE) in the 3' untranslated region which govern their expression. We have previously shown that HuR, an RNA regulator that binds to AREs, plays a major positive role in regulating inflammatory cytokine production in glia. HuR is predominantly nuclear in localization but translocates to the cytoplasm to exert a positive regulatory effect on RNA stability and translational efficiency. Homodimerization of HuR is necessary for translocation and we have developed a small molecule inhibitor, SRI-42127, that blocks this process. Here we show that SRI-42127 suppressed HuR translocation in LPS-activated glia in vitro and in vivo and significantly attenuated the production of pro-inflammatory mediators including IL1β, IL-6, TNF-α, iNOS, CXCL1, and CCL2. Cytokines typically associated with anti-inflammatory effects including TGF-β1, IL-10, YM1, and Arg1 were either unaffected or minimally affected. SRI-42127 suppressed microglial activation in vivo and attenuated the recruitment/chemotaxis of neutrophils and monocytes. RNA kinetic studies and luciferase studies indicated that SRI-42127 has inhibitory effects both on mRNA stability and gene promoter activation. In summary, our findings underscore HuR's critical role in promoting glial activation and the potential for SRI-42127 and other HuR inhibitors for treating neurological diseases driven by this activation.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.

Optimizing treatment for patients with low-grade gliomas should focus on the role of radiation and chemotherapy, as well as the prognostic impact of molecular diagnostics (1p/19q and IDH status). For anaplastic oligodendroglioma, focus should be placed on molecular markers (particularly 1p/19q status) and combination treatment with chemotherapy (temozolomide or PCV [procarbazine, lomustine, and vincristine]) and radiation. For patients with malignant glioblastomas, the role of methylguanine methyl-transferase (MGMT) methylation status has become increasingly important to treatment decisions. MGMT methylation status should be considered in elderly patients and/or those with low performance status (methylated patients benefit from temozolomide) and a hypofractionated radiation schedule should be used.

Purpose: Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma. Patients and Methods: In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2. Results: Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control (P = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32–0.88; two-sided log-rank P = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; P = 0.38)], median duration of response [7.8 months (95% CI, 3.5–22.2) vs. 5.6 (95% CI, 3.7–7.4)], and ability to discontinue steroids for ≥6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07–0.45; P < 0.0001). Conclusions: Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM. See related commentary by Wick and Wagener, p. 1535

Background: H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults. While radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available and current standard of care is RT followed by monitoring. Dordaviprone (ONC201), a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of five open-label trials previously demonstrated efficacy in dordaviprone-treated patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating dordaviprone in patients with H3 K27M-mutant disease. Methods: ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of dordaviprone in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy will be randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on two consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed by response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with additional sites to be open internationally in 2023. Citation Format: Isabel Arrillaga-Romany, Andrew Lassman, Susan L. McGovern, Sabine Mueller, Louis B. Nabors, Martin van den Bent, Michael Vogelbaum, Joshua E. Allen, Allen S. Melemed, Rohinton S. Tarapore, Dewen Yang, Patrick Wen, Timothy Cloughsey. ACTION: A randomized phase 3 study of dordaviprone (ONC201) in patients with newly diagnosed H3 K27M-mutant diffuse glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT060.

Therapeutic advances for glioblastoma have been minimal over the past 2 decades. In light of the multitude of recent phase III trials that have failed to meet their primary endpoints following promising preclinical and early-phase programs, a Society for Neuro-Oncology Think Tank was held in November 2020 to prioritize areas for improvement in the conduct of glioblastoma clinical trials. Here, we review the literature, identify challenges related to clinical trial eligibility criteria and trial design in glioblastoma, and provide recommendations from the Think Tank. In addition, we provide a data-driven context with which to frame this discussion by analyzing key study design features of adult glioblastoma clinical trials listed on ClinicalTrials.gov as “recruiting” or “not yet recruiting” as of February 2021.

Background Glioblastoma (GBM) has a 5-year survival rate of 3%-5%. GBM treatment includes maximal resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ). Cytochrome C oxidase (CcO) is a mitochondrial enzyme involved in the mechanism of resistance to TMZ. In a prior retrospective trial, CcO activity in GBMs inversely correlated with clinical outcome. The current Cyto-C study was designed to prospectively evaluate and validate the prognostic value of tumor CcO activity in patients with newly diagnosed primary GBM, and compared to the known prognostic value of MGMT promoter methylation status. Methods This multi-institutional, blinded, prospective biomarker study enrolled 152 patients with newly diagnosed GBM who were to undergo surgical resection and would be candidates for standard of care. The primary end point was overall survival (OS) time, and the secondary end point was progression-free survival (PFS) time. Tumor CcO activity and MGMT promoter methylation status were assayed in a centralized laboratory. Results OS and PFS did not differ by high or low tumor CcO activity, and the prognostic validity of MGMT promoter methylation was confirmed. Notably, a planned exploratory analysis suggested that the combination of low CcO activity and MGMT promoter methylation in tumors may be predictive of long-term survival. Conclusions Tumor CcO activity alone was not confirmed as a prognostic marker in GBM patients. However, the combination of low CcO activity and methylated MGMT promoter may reveal a subgroup of GBM patients with improved long-term survival that warrants further evaluation. Our work also demonstrates the importance of performing large, multi-institutional, prospective studies to validate biomarkers. We also discuss lessons learned in assembling such studies.

Background Response to targeted therapy varies between patients for largely unknown reasons. Here, we developed and applied an integrative platform using mass spectrometry imaging (MSI), phosphoproteomics, and multiplexed tissue imaging for mapping drug distribution, target engagement, and adaptive response to gain insights into heterogeneous response to therapy. Methods Patient-derived xenograft (PDX) lines of glioblastoma were treated with adavosertib, a Wee1 inhibitor, and tissue drug distribution was measured with MALDI-MSI. Phosphoproteomics was measured in the same tumors to identify biomarkers of drug target engagement and cellular adaptive response. Multiplexed tissue imaging was performed on sister sections to evaluate spatial co-localization of drug and cellular response. The integrated platform was then applied on clinical specimens from glioblastoma patients enrolled in the phase 1 clinical trial. Results PDX tumors exposed to different doses of adavosertib revealed intra- and inter-tumoral heterogeneity of drug distribution and integration of the heterogeneous drug distribution with phosphoproteomics and multiplexed tissue imaging revealed new markers of molecular response to adavosertib. Analysis of paired clinical specimens from patients enrolled in the phase 1 clinical trial informed the translational potential of the identified biomarkers in studying patient’s response to adavosertib. Conclusions The multimodal platform identified a signature of drug efficacy and patient-specific adaptive responses applicable to preclinical and clinical drug development. The information generated by the approach may inform mechanisms of success and failure in future early phase clinical trials, providing information for optimizing clinical trial design and guiding future application into clinical practice.

Background High-dose methotrexate (HD-MTX) has broad use in the treatment of central nervous system (CNS) malignancies but confers significant toxicity without inpatient hydration and monitoring. Glucarpidase is a bacterial recombinant enzyme dosed at 50 units (u)/kg, resulting in rapid systemic MTX clearance. The aim of this study was to demonstrate feasibility of low-dose glucarpidase to facilitate MTX clearance in patients with CNS lymphoma (CNSL). Methods Eight CNSL patients received HD-MTX 3 or 6 g/m2 and glucarpidase 2000 or 1000u 24 h later. Treatments repeated every 2 weeks up to 8 cycles. Results Fifty-five treatments were administered. Glucarpidase 2000u yielded > 95% reduction in plasma MTX within 15 min following 33/34 doses (97.1%) and glucarpidase 1000u yielded > 95% reduction following 15/20 doses (75%). Anti-glucarpidase antibodies developed in 4 patients and were associated with MTX rebound. In CSF, glucarpidase was not detected and MTX levels remained cytotoxic after 1 (3299.5 nmol/L, n = 8) and 6 h (1254.7 nmol/L, n = 7). Treatment was safe and well-tolerated. Radiographic responses in 6 of 8 patients (75%) were as expected following MTX-based therapy. Conclusions This study demonstrates feasibility of planned-use low-dose glucarpidase for MTX clearance and supports the hypothesis that glucarpidase does not impact MTX efficacy in the CNS. Clinical trial registration NCT03684980 (Registration date 26/09/2018).

Introduction: Lymphodepletion is a key factor for responses in both autologous and allogeneic cell therapies. We are currently evaluating in a Phase I trial, the combination of Temozolomide (TMZ) chemotherapy with methylguanine-DNA methyltransferase (MGMT) modified γδ T cells (Drug Resistant Immunotherapy, or DRI) during maintenance TMZ in patients receiving the Stupp protocol. In this report, we examine both DRI graft and circulating lymphocyte phenotype and function during the treatment phase. Methods: Patients meeting enrollment criteria undergo tumor resection, placement of a Rickham catheter in the tumor cavity, and an apheresis collection immediately prior to standard chemoradiotherapy (CRT). DRI follows TMZ on Day 1 of maintenance and consists of 150mg/m2 IV TMZ and concurrent intracranial injection of 1.0 x 107 DRI γδT cells. Peripheral blood (PB) was collected at apheresis and immediately prior to the start of each 28-day maintenance cycle. Flow cytometric (FACS) analysis of PB and DRI grafts using antibodies to CD3, CD4, CD8, CD16/56, CD19, TCR-γδ, Vδ1, Vδ2, CD197, CD27, CD28, CD57, CD45RA, Th1/Th2/Th17 PB serum cytokines, and DRI cytotoxic graft function were obtained. When applicable, FFPE sections of recurrent resected GBM tissues were examined for immune infiltration. Results: DRI grafts contained 74-93% activated γδ T cells with 0.3-0.5 MGMT copies/cell. Cytotoxicity against K562 ranged from 30% to 75% at 40:1 (E:T). Peripheral lymphodepletion was evident throughout TMZ treatment in the Stupp protocol. T cell counts fell precipitously after CRT and cycle 1 (1647+774 vs 609+214 cells/mL) and remained low throughout maintenance phase (range 214-1450 T cells/mL). NK counts remained normal and showed uneven recovery through the first three cycles but failed to recover for the remainder of maintenance phase. γδ T cells also recovered modestly through the first two cycles but failed to recover after additional cycles. Interestingly, CD45RA+CD27- effector T cells showed only slight increases for each patient throughout TMZ maintenance. Cytokine analysis did not show a clear trend except for consistent T cell expression of perforin and IP-10. One patient with recurrent GBM was successfully resected 110d following DRI. Histopathology revealed widespread necrosis with significant infiltration of CD4+ and CD8+ T cells and γδ T cells in the tumor parenchyma. Conclusions: Standard of care TMZ is lymphodepleting and DRI therapy can be conducted in an environment favorable to T cell persistence and sustained immune response. One treated patient demonstrated infiltration of both αβ and γδ T cells 110 days following a single dose of DRI γδ T cells. TMZ maintenance during the Stupp regimen prolongs lymphodepletion, thereby presenting a favorable setting for adoptive cell therapy. Citation Format: Lawrence S. Lamb, Lei Ding, Ryan C. Miller, Mariska ter Haak, Caitlyn Lucas, Becca Weekley, Samantha Youngblood, Cathy Langford, Guoling Chen, Louis B. Nabors. Maintenance-phase Temozolomide as a lymphodepletion platform for intracranialadoptiveγδ T cell-basedtherapy in primary high-grade gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1173.

2044 Background: γδ T cells, MHC unrestricted immune cells, target NKG2D ligands differentially expressed on tumor cells. DeltEx drug resistant immunotherapy (DRI), a novel ex vivo expanded, activated γδ T cell expresses MGMT, conveying TMZ resistance. NCT04165941 , a phase 1 trial assessing the safety of single and multiple infusions of autologous DeltEx DRI cells presents updated safety and efficacy data. Methods: Adult newly diagnosed GBM patients with adequate organ function and KPS≥70% are enrolled. Cells engineered from apheresis after tumor resection were infused through a Rickham catheter placed during surgery. Cohort (C) 1, 2 and 3 receive 1, 3 and 6 doses of cells respectively on day (D) 1 of each 28-day maintenance cycle. Patients receive 1 x 107 γδ T cells intratumorally on D1 with 150 mg/m2 of TMZ intravenously with the Stupp regimen. Primary endpoint is safety; secondary endpoints include progression free and overall survival. Immunologic and genomic correlative analyses are being conducted. Dose limiting toxicities (DLTs) are defined as treatment related ≥ grade 3 cardiopulmonary or hepatic toxicity, grade 4 toxicity exceeding 72 hours or neurologic deterioration that exceeds 2 weeks. Results: 12 patients (58% male; median age 66.5 (range: 21-76); 66.7% IDH-WT, 66.7% MGMT unmethylated) were enrolled with 6 dosed (3 in C1, 3 in C2). No patients had DLTs, cytokine release syndrome (CRS), or neurotoxicity. The most common adverse events (AEs) were Grade 1/2 events including fever, leukopenia, nausea, and vomiting attributable to TMZ or radiotherapy. One subject had Grade 3 treatment related AEs of UTI, dehydration, and thrombocytopenia. Three evaluable C1 patients have PFS of 8.3, 11.9, 7.4 months and OS of 15.6, 17.7 and 9.6 months respectively. In C2, three patients have been dosed, with one patient with stable disease at 8.2 months after receiving all three doses and no DLTs. Patient recruitment continues with anticipated completion in 2022. Conclusions: Data demonstrates that single, repeat doses of DRI T cells have manageable toxicity with encouraging trend in PFS.

This study explores the repeated use of glucarpidase following HD-MTX in patients with CNSL. HD-MTX requires aggressive hydration and inpatient monitoring to prevent toxicity. Glucarpidase 50 units(u)/kg for delayed MTX clearance results in a reduction of systemic MTX levels without crossing the blood brain barrier. This study explores the use of 1000 or 2000 units of glucarpidase following repeated cycles of MTX 3–8 g/m2. Eligible adult patients had isolated CNSL, CrCl ≥ 60 mL/min, and KPS ≥ 50. Rituximab with MTX was administered for eight cycles. Glucarpidase was given 24 hours after each MTX infusion. MTX concentrations were monitored in serum and cerebrospinal fluid (CSF). Twelve patients enrolled to date and data are available for 50 doses of MTX (3 g/m2 (20), 6 g/m2 (21), 8 g/m2 (9)). Glucarpidase 1000u (14) or 2000u (36) resulted in at least a 95% reduction in serum MTX levels within 15 minutes following 49/50 doses. A 93% decrease was seen with the remaining dose. Glucarpidase was not detected in the CSF of 7 patients analyzed. Potentially cytotoxic MTX concentrations (10–6 M) were observed in CSF 1 hour (7/7) and 6 hours (4/7) after glucarpidase administration. Radiographic responses are evaluable in 9 patients: complete response (5), partial response (2), stable disease (1), and progressive disease (1). No grade 3 events were attributed to glucarpidase; one grade 4 event of anaphylaxis occurred. Anti-glucarpidase antibodies were detected in 2/5 patients analyzed. In summary, administration of low-dose glucarpidase 24 hours after MTX 3–8 g/m2 results in a reproducible rapid reduction in serum MTX levels in non-renally impaired patients. CSF MTX levels remain therapeutic and clinical response expected from MTX-based therapy does not appear compromised. Anti-glucarpidase antibodies may develop though significance remains unclear. Study is ongoing. Future directions will explore glucarpidase use for reduction of inpatient stay with HD-MTX.

BACKGROUND CC-115 is an oral, CNS-penetrant, selective inhibitor of mammalian target of rapamycin kinase (mTOR) and deoxyribonucleic acid-dependent protein kinase (DNA-PK). Both targets are important in glioblastoma; PI3K/Akt/mTOR signaling is hyperactive in most glioblastomas, and DNA-PK is integral to repair of radiotherapy-mediated DNA damage. To investigate CC-115 in newly diagnosed glioblastoma and explore potential genomic biomarker associations, CC-115 was evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial, an adaptive platform trial designed to efficiently test experimental agents. METHODS Adults with newly diagnosed MGMT-unmethylated glioblastoma, with genomic data available, are eligible for this ongoing trial. Patients are adaptively randomized to one of several experimental arms or the control arm: standard radiotherapy with concurrent and adjuvant temozolomide. The primary endpoint is overall survival (OS). Patients randomized to CC-115 (10mg po BID) received it concurrently with radiotherapy and as adjuvant monotherapy. As the first in-human use of CC-115 with radiation, a safety lead-in 3 + 3 design was used. RESULTS Twelve patients were randomized to CC-115; seven patients had possible treatment-related CTCAE grade > 3 toxicity, including four pre-specified dose-limiting toxicities: liver function abnormality (n=1), hyperlipidemia (n=1), lipase elevation (n=1) and cerebral edema (n=1). There was no significant difference in progression-free survival (PFS, median 4.2 months [CC-115] vs. 5.2 months, p=0.9) or OS (median 10.1 months [CC-115] vs. 14.5 months, p=0.9) compared to the 50 patients randomized to the control arm. Based on early PFS results, randomization probability to CC-115 decreased from 25% to < 10% at time of the trial arm closure. CONCLUSION Concurrent and adjuvant CC-115 was associated with toxicity and failed to improve PFS or OS. The INSIGhT trial design allowed for more efficient testing of CC-115, decreasing patients and resources allocated to a therapy that was discontinued due to concerns about toxicity and unfavorable risk-to-benefit ratio.

Although immunotherapy works well in glioblastoma (GBM) pre-clinical mouse models, the therapy has not demonstrated efficacy in GBM patients. Since recent studies have linked the gut microbial composition to the success with immunotherapy for other cancers, we utilized a novel humanized microbiome (HuM) model in order to study the response to immunotherapy in a pre-clinical mouse model of GBM. We used five healthy human donors for fecal transplantation of gnotobiotic mice since it is now recognized that microbe strain level differences render individual humans with a unique microbial community composition. After the transplanted microbiomes stabilized, the mice were bred to generate 5 independent humanized mouse lines (humanized microbiome HuM1-HuM5). Analysis of shotgun metagenomic sequencing data from fecal samples revealed a unique microbiome composition with significant differences in diversity and microbial composition among HuM1-HuM5 lines. We next analyzed the growth of intracranial glioma cells in the HuM lines. All HuM mouse lines were susceptible to GBM transplantation, and exhibited similar median survival ranging from 19-26 days. Interestingly, we found that HuM lines responded differently to the immune checkpoint inhibitor anti-PD-1. Specifically, we demonstrate that HuM1, HuM4, and HuM5 mice are non-responders to anti-PD-1 resulting in the death of the mice from the intracranial tumors, while HuM2 and HuM3 mice are responsive to anti-PD-1 and displayed significantly increased survival compared to isotype controls. Bray-Curtis cluster analysis of the 5 HuM gut microbial communities revealed that HuM2 and HuM3 were closely related. Detailed taxonomic comparison analysis at the top 5 across all HuM mouse lines revealed that Bacteroides cellulosilyticus was commonly found between HuM2 and HuM3 with high abundances. The results of our study establish the utility of humanized microbiome mice as avatars to delineate features of the host interaction with gut microbe communities needed for effective immunotherapy against GBM.

The development of novel therapeutics that exploit alterations in the activation state of key cellular signaling pathways due to mutations in upstream regulators has generated the field of personalized medicine. These first-generation efforts have focused on actionable mutations identified by deep sequencing of large numbers of tumor samples. We propose that a second-generation opportunity exists by exploiting key downstream “nodes of control” that contribute to oncogenesis and are inappropriately activated due to loss of upstream regulation and microenvironmental influences. The RNA-binding protein HuR represents such a node. Because HuR functionality in cancer cells is dependent on HuR dimerization and its nuclear/cytoplasmic shuttling, we developed a new class of molecules targeting HuR protein dimerization. A structure–activity relationship algorithm enabled development of inhibitors of HuR multimer formation that were soluble, had micromolar activity, and penetrated the blood–brain barrier. These inhibitors were evaluated for activity validation and specificity in a robust cell-based assay of HuR dimerization. SRI-42127, a molecule that met these criteria, inhibited HuR multimer formation across primary patient-derived glioblastoma xenolines (PDGx), leading to arrest of proliferation, induction of apoptosis, and inhibition of colony formation. SRI-42127 had favorable attributes with central nervous system penetration and inhibited tumor growth in mouse models. RNA and protein analysis of SRI-42127–treated PDGx xenolines across glioblastoma molecular subtypes confirmed attenuation of targets upregulated by HuR. These results highlight how focusing on key attributes of HuR that contribute to cancer progression, namely cytoplasmic localization and multimerization, has led to the development of a novel, highly effective inhibitor. Significance: These findings utilize a cell-based mechanism of action assay with a structure–activity relationship compound development pathway to discover inhibitors that target HuR dimerization, a mechanism required for cancer promotion.

Background Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody–drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM. Methods M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5–1.5 mg/kg) on days 1 and 15, and TMZ (150–200 mg/m2) on days 1–5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve. Results There were 60 patients, median age 56 years (range, 20–79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%. Conclusions Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).

BackgroundBrain tumors can present as focal neurologic deficits (reflecting the tumor location) or generalized symptoms due to increased intracranial pressure. Occasionally, brain tumors can be found incidentally in asymptomatic patients or in patients with unrelated symptoms who undergo brain imaging. The term incidentaloma is used to refer to these imaging abnormalities.ObjectiveThe object of this study was to examine the prevalence and correlates of asymptomatic glioma in a large epidemiological study of brain tumors.MethodsThe analysis was based on a large series of patients with glioma (N = 1989) enrolled in a multicenter clinic-based epidemiologic study between 2005 and 2017. Patients were considered asymptomatic from the tumor, and thus as having an incidentally detected glioma (IDG), if the tumor was diagnosed during workup of injury or unrelated medical condition.ResultsA total of 32 of 1989 (1.6%) patients were asymptomatic at diagnosis. The leading indication for brain imaging in IDG was non-workplace injuries followed by medical workup for unrelated conditions. IDG was more prevalent in patients younger than 50 years of age (2.6% vs 1.0%). IDG was also more common in patients with low grade gliomas (4.7% for WHO grade II and 1.5% for WHO grade III) vs glioblastomas (0.6% in WHO grade IV).ConclusionThe present data suggest that gliomas may be found incidentally, especially among low grade gliomas. Studies of IDG may be useful as a proxy for early detection of tumor as a means to improve patient survival.

Glioblastoma (GBM) is a malignant and aggressive brain tumor with a median survival of ∼15 months. Resistance to treatment arises from the extensive cellular and molecular heterogeneity in the three major components: glioma tumor cells, glioma stem cells, and tumor-associated microglia and macrophages. Within this triad, there is a complex network of intrinsic and secreted factors that promote classic hallmarks of cancer, including angiogenesis, resistance to cell death, proliferation, and immune evasion. A regulatory node connecting these diverse pathways is at the posttranscriptional level as mRNAs encoding many of the key drivers contain adenine- and uridine rich elements (ARE) in the 3' untranslated region. Human antigen R (HuR) binds to ARE-bearing mRNAs and is a major positive regulator at this level. This review focuses on basic concepts of ARE-mediated RNA regulation and how targeting HuR with small molecule inhibitors represents a plausible strategy for a multi-pronged therapeutic attack on GBM.

Gliomas are the most common type of malignant primary brain tumor and few risk factors have been linked to their development. Handedness has been associated with several pathologic neurological conditions such as schizophrenia, autism, and epilepsy, but few studies have evaluated a connection between handedness and risk of glioma. In this study, we examined the relationship between handedness and glioma risk in a large case-control study (1,849 glioma cases and 1,354 healthy controls) and a prospective cohort study (326,475 subjects with 375 incident gliomas). In the case-control study, we found a significant inverse association between left handedness and glioma risk, with left-handed persons exhibiting a 35% reduction in the risk of developing glioma (Odds Ratio (OR)=0.65, 95% Confidence Interval (CI): 0.51, 0.83) after adjustment for age, gender, race, education, and state of residence; similar inverse associations were observed for GBM (OR=0.69, 95% CI: 0.52, 0.91), and non-GBM (OR=0.59, 95% CI: 0.42, 0.82) subgroups. The association was consistent in both males and females, and across age strata, and was observed in both glioblastoma and in lower grade tumors. In the prospective cohort study, we found no association between handedness and glioma risk (Hazards Ratio=0.92, 95% CI: 0.67, 1.28) adjusting for age, gender, and race. Further studies on this association may help to elucidate mechanisms of pathogenesis in glioma.

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.

Infection with SARS CoV-2 virus has resulted in a global pandemic of COVID-19, a respiratory illness with a crude mortality rate of 3–4%. Risk of death is higher in the elderly and in patients with underlying comorbid conditions. When local incidence of COVID-19 is high, hospital resources are scarce and elective admissions and procedures are placed on hold. Patients with CNSL receiving first-line HD-MTX require admission for monitoring and aggressive hydration to prevent toxicity. This study explores the feasibility of planned-use glucarpidase, a recombinant bacterial enzyme that rapidly reduces serum MTX levels, to facilitate outpatient administration of HD-MTX. Eligible adult patients had isolated CNSL and had previously tolerated inpatient HD-MTX. MTX 3.5 g/m2 was administered in the outpatient setting with hydration. Patients returned 24 hours after MTX administration for glucarpidase 2000u and additional hydration. MTX level was determined by high pressure liquid chromatography (HPLC) 48 hours following MTX administration. To date, seven outpatient HD-MTX treatments have been administered to a total of three patients. In all cases, MTX levels were reduced to < 100 nmol/L at 48 hours. Three treatments resulted in grade 1 elevation of AST/ALT (two patients). One treatment resulted in a grade 2 creatinine increase. Creatinine returned to baseline following additional outpatient hydration. No patients required hospital admission. This study demonstrates feasibility of outpatient HD-MTX administration with planned-use glucarpidase during the COVID-19 pandemic. We are currently enrolling to a larger study of planned-use glucarpidase for repeated doses of outpatient HD-MTX.

Glioblastoma is the most common and most aggressive primary brain tumor in adults. Glioblastoma was the first neoplasm to be systemically studied by The Cancer Genome Atlas and is one of the most molecularly well-characterized tumors in humans. Molecular profiling of glioblastoma is increasingly available and had led to the identifications of multiple prognostic factors as well as potential actionable targets for novel therapies. We identified 145 patients diagnosed with glioblastoma whose tumor tissue was analyzed using next generation sequencing (NGS). The NGS was performed using validated, commercially available panels. We studied somatic genetic alterations with a particular focus on TERT (which was altered in 55.9% of patients in the dataset), CDKN2A (44%), TP53 (39%), EGFR (38.6%), PTEN (31%), IDH1 (20%), and CDK4 (9%). These molecular alterations were analyzed in relation to the patients’ tumor locations, demographics, and outcomes. We used multiple binary logistic regressions to assess whether demographics and tumor location were predictive of the above alterations We also assessed the relationship between molecular alterations and outcomes when controlling for treatment and demographic variables. Among demographic variables, age predicted alterations in IDH1, EGFR, TERT, TP53, and PTEN. Frontal lobe tumors were more likely to be IDH1-mutated, irrespective of patient age. Sex and race did not predict the incidence of the molecular alterations of interest. Analysis of outcomes revealed that, when controlling for treatment and demographic variables, TERT promoter mutations, TP53 nonsense mutations, and EGFR A289V were predictive of a decreased progression-free survival, while CDKN2A deletion, PTEN missense mutations, and EGFR A289V were predictive of decreased overall survival. Our experience highlights the importance of incorporating routine NGS in the management of patients with glioblastoma. More studies are required to evaluate the predictive and/or prognostic values of different molecular alterations.

BACKGROUND The EMulate Therapeutics Voyager system is an investigational non-sterile, non-invasive, non-thermal, non-ionizing, portable, home-use medical device that uses a specific, localized ultra-low radio frequency energy (ulRFE®) cognate for the treatment of brain cancer. METHODS This ongoing, open-label, multi-center study (NAT-101) is being conducted in the US and Australia in patients with recurrent GBM. There are 3 treatment groups: 32 patients treated with Voyager alone, 43 patients treated with Voyager + Investigator’s choice of anti-cancer therapy, and 21 patients treated with Voyager+lomustine+/-bevacizumab. The objective of the study is to assess if the Voyager is a safe and feasible treatment for recurrent GBM. The primary outcome measure is safety, assessed by the incidence and evaluation of adverse events (AEs) associated with the Voyager. The secondary outcome measures are progression-free survival and overall survival. RESULTS Enrollment is closed, and long-term treatment and follow-up is ongoing. 96 patients were enrolled and treated. 82 patients reported at least one AE, and 18 AEs were assessed as device-related (mild-moderate; 12 headache, 2 vomiting, 1 nausea, 1 confusion, 1 insomnia, and 1 skin irritation). 31 patients reported at least one serious AE, and none were assessed as device-related. 33% of patients treated with Voyager alone and 36% of patients treated with Voyager + chemotherapy were progression-free after 6 months. 58% of patients treated with Voyager alone and 60% of patients treated with Voyager + chemotherapy remained alive after 6 months; median overall survival is 7 months (95% CI=4.4±14.3) in patients treated with Voyager alone and 10 months (95% CI=6.7±11.5) in patients treated with Voyager + chemotherapy. CONCLUSIONS The Voyager system appears to be safe and feasible for the treatment of recurrent GBM. Given that therapy is delivered non-invasively and no device-related serious adverse events were reported, further prospective study of the investigational device is planned.

OBJECTIVE To investigate medical decision-making capacity (MDC) in patients with advanced stage cancer. METHODS Participants were 113 newly diagnosed adults with brain metastases and 41 adults with metastatic cancer without brain metastases who were recruited from an academic medical center and 40 demographically-matched healthy controls recruited from the community. We evaluated MDC using the Capacity to Consent to Treatment Instrument (CCTI) Vignette B and its four clinically relevant consent standards (expressing a treatment choice, appreciation, reasoning, and understanding). Capacity impairment ratings (no impairment, mild/moderate impairment, and severe impairment) on the consent standards were also assigned to each participant using cutoff scores derived statistically from the performance of the control group. RESULTS Both of the metastatic cancer groups (with and without brain metastasis) performed significantly below controls on consent standards of understanding and reasoning. The brain metastasis group performed below the non-metastatic cancer group on understanding. Capacity compromise was defined as performance ≤1.5 standard deviations (SD) below the control group mean. Using this definition, approximately 65% of the participants with brain metastases and 51% of participants with metastatic cancer without brain metastases were impaired on at least one MDC standard. CONCLUSION Over half of participants with metastatic cancer regardless of whether they have brain disease have reduced capacity to make treatment decisions. The finding of impaired MDC in patients without brain metastases is surprising and suggests this group likely exhibits cognitive deficits that impact their ability to understand and reason about different treatment options. This finding suggests that clinicians need to carefully consider the patient’s ability to engage in treatment decision making when they are discussing treatment options for metastatic cancer. These results also indicate a need for the development and investigation of interventions to support MDC in this patient population.

The highly infiltrative nature of glioblastoma (GBM) underscores limited response to current therapies and subsequent unfavorable clinical outcome. Despite the gross total resection of tumors located in the enhancing lesions, GBMs inevitably recur from the areas adjacent to the resection cavity that retains tumor cells with tumor-initiating capacity with therapy resistant nature (glioma-initiating cells: GICs). Here, we identified, in clinical GBM tumors, two mutually-exclusive glioma-initiating cell subpopulations in two different regions of GBM tumors, core- and edge-located glioma-initiating cells that co-exist in single tumors (Minata et al. Cell Reports. 2019). Following this observation, we further established patient-derived GBM clones from both tumor core and edge tissues, termed core-GICs and edge-GICs, and uncovered their distinct molecular signatures. Unexpectedly, we found that these two distinct GIC subpopulations retain the spatial identity, meaning that the core GICs locate themselves in the injected site, whereas the edge GICs initiated to form edge-like lesions, when xenografted into mouse brains. Through OMICs analyses, we identified CD38 as a key molecule to determine the edge phenotype both in vitro and in vivo. Collectively, our findings indicate, for the first time, that GBM cells are heterogeneous to be composed of tumor cells destined to be located in distinct regions of the tumors in a molecularly-defined manner.

BACKGROUND Temozolomide forms O6-methylguanine (O6mG), 7-methylguanine (N7mG), and 3- methyladenine (N3mA) DNA adducts. The O6mG DNA adduct is repaired by MGMT. N7mG and N3mA DNA adducts are removed by the base excision repair (BER) pathway, initiated by N- methylpurine DNA glycosolase (MPG). TRC-102 is a BER inhibitor that binds to the apurinic site created through the action of MPG. METHODS A phase II study of adult glioblastoma in first recurrence was performed in the Adult Brain Tumor Consortium with temozolomide, 150 mg/ m2 and TRC-102, 150 mg (1–5/ 28 days). Primary objective included radiographic response rate. Secondary objectives included safety and PFS-6. Exploratory objectives included tumor expression of N-methylpurine DNA glycosylase (MPG). The study tested hypothesis that combination therapy will achieve 30% RR. To understand the context of vulnerability to TRC102 we performed RNA sequencing on treatment naïve tissue from 7 patients. RESULTS Nineteen patients were enrolled in first stage. Median age was 60 years (range: 48–76), 53% females, median KPS was 80 (range: 70–90). Median cycles of treatment was 2 (range: 1–12). No responses were observed. Median OS was 11.0 months (95% CI: 8–18 months), median PFS was 2.0 months (95% CI: 1.8–3.6 months). PFS-6 rate was 10.5 % (2/19). The combination was safe. MPG staining was negative in six, 1+ in five and 2+ in three patients. PFS of 11 + months in two patients (exceptional responders) was associated with MPG expression. Preliminary analysis on RNA sequencing revealed significant enrichment for DNA Damage Response pathways (MsigDB), chromosomal instability gene signature (CIN70 and CIN25), and proliferative gene signature (PCNA25) in these 2 patients. CONCLUSIONS TRC 102 with temozolomide has acceptable safety but did not meet the primary endpoint of response. Gene signature of MsigDB, CIN70, CIN25 and PCNA25 was seen in exceptional responders and biomarker driven study is planned.

Meningiomas represent a full spectrum of tumors that are the most common type of brain tumor in adults. Although most are benign, recent research has shown that the recurrence rate is high, especially for WHO grades 2 and 3, and overall survival is poor for these grades. Treatment is evolving, and recently sunitinib and bevacizumab have shown promise compared with historical treatments. However, more research is needed to identify better treatments for meningiomas. Treatment of brain metastases is another evolving field. Studies suggest that stereotactic radiosurgery is preferable to whole-brain radiation therapy and that immune checkpoint inhibitors and therapies targeted to the T790M mutation and ALK can improve outcomes in patients with non-small cell lung cancer and brain metastases.

2057 Background: Temozolomide (TMZ) transiently upregulates NKG2D ligands targeted by innate immune effector cells. Lymphodepletion impairs this immune response, however, genetic modification of ex vivo expanded γδ T cells with an MGMT-expressing lentivector confers resistance to TMZ, allowing concurrent chemotherapy and γδ T cell infusion, thereby targeting the tumor when NKG2DL are maximally expressed. This Drug Resistant Immunotherapy (DRI) is currently being evaluated in a Phase 1 first in human study (NCT04165941) and interim safety and biologic correlative analysis are detailed here for the first dosing cohort. Methods: Adults with newly diagnosed, untreated glioblastoma (GBM), adequate organ function, and a KPS≥70% will be enrolled. Subjects undergo subtotal resection and placement of a Rickham reservoir followed 3-4 weeks by apheresis from which γδ T cells are expanded, transduced with an MGMT-expressing lentivector, harvested, and cryopreserved. Standard of care induction TMZ/radiation therapy is initiated followed by 6 cycles of maintenance TMZ. Intravenous TMZ (150mg/m2) and intracranial dosing of 1 x 107 γδ T cells occur on day 1 of each maintenance cycle. Daily oral TMZ 150mg/m2 follows for Days 2-5. Dose level 1 (DL1) subjects receive 1 fixed dose of γδ T cells and DL2 receive 3 doses administered on Day 1 of each of first 3 cycles of TMZ dependent on absence of dose limiting toxicity. Primary endpoint is safety; secondary endpoints include progression free and overall survival. Immunologic and genomic correlative analyses are being conducted at specific time points from peripheral blood and cerebral spinal fluid collected from the Rickham. Results: Six subjects (4 females, 2 males) have been enrolled in DL1. All subjects were IDH1-WT with 5 subjects MGMT unmethylated and 1 methylated. Of these, 1 generated inadequate gd T cells and 2 withdrew consent prior to DRI treatment. For the 3 that received DRI, treatment-related adverse events with maximum CTCAE Grade 3 occurred in 1 subject; UTI, dehydration, and thrombocytopenia. The most common Grade 1/2 events included: fever, leukopenia, nausea, and vomiting which were attributable to TMZ or radiotherapy. Circulating T cells remained below normal range throughout maintenance phase in 2/3 subjects. NK and gd T cell numbers remained within low normal range for 3/3 and 2/3 subjects, respectively. Serum Th1 (IFNg, IL-2, TNFa) and Th2 (IL4, IL5, IL-10) cytokines were within clinical range although TNFa remained elevated from the gdT cell infusion through day +30 in 2 subjects. Conclusions: Administration of MGMT-gene modified gdT cells and TMZ as DRI is feasible in lymphodepleted subjects during TMZ maintenance phase and sufficiently safe to warrant further investigation at additional doses. Clinical trial information: NCT04165941.

2016 Background: Among the primary aims of new therapies for glioblastoma (GBM) are the reduction of morbidity and restoration or preservation of quality of life (QoL). Selinexor (SEL) is a first-in class, oral, selective inhibitor of nuclear export which blocks exportin 1 (XPO1), forcing the nuclear retention and reactivation of tumor suppressor proteins, ultimately causing cell death in cancer cells. SEL is approved for the treatment of previously treated multiple myeloma and DLBCL. XPORT-GBM-029 (NCT04421378) is a phase 1 dose finding study followed by an open-label randomized phase 2, 3-arm trial to evaluate SEL in combination with standard therapies for newly diagnosed and recurrent GBM: Arm A (ndGBM, uMGMT) – radiation +/- SEL; Arm B (ndGBM, mMGMT) – radiation and temozolomide +/- SEL; Arm C (rGBM) – lomustine +/- SEL at first relapse. We look to identify sensitive, reliable, and clinically meaningful digital assessments of the functional status of ndGBM and rGBM patients via a patient-centric approach. Methods: XPORT-GBM-029 incorporates standard clinical and imaging evaluations of GBM progression with novel digital tools that objectively measure motor and cognitive function. The study is conducted at 50 sites globally with the aim of enrolling 350 patients with newly diagnosed and recurrent GBM. Following discussions with KOLs and patient advocacy partners at EndbrainCancer, we surveyed GBM patients and their caregivers to identify disease manifestations critical to patients’ QoL. The survey revealed four key areas impacting patients’ QoL that can be affected by GBM therapies and can be objectively monitored: cognitive function, lateralization, fatigue, and sleep. In this trial we use objective measurements to evaluate SEL’s effects on GBM patients’ QoL. Patients wear inertial sensors to measure their activity and sleep and complete a cognitive battery at baseline and before each MRI. Results: Associations between objective digital measures of activity, gait, fatigue, sleep, and cognition will be examined with respect to clinical assessments including physical examinations, modified Response Assessment in Neuro-Oncology (mRANO), Neurologic Assessment in Neuro-Oncology (NANO), Karnofsky Performance Score (KPS) and Patient Reported Outcome (PRO) QoL questionnaires. Descriptive summary statistics and plots are employed in exploratory data analysis, and other advanced data mining methods may also be considered. Conclusions: XPORT-GBM-029 trial is probably the first large, prospective, longitudinal study in GBM patients employing digital markers and may provide useful information regarding the utility of wearable and mobile devices for measuring functional outcomes in clinical trials. Clinical trial information: NCT04421378.

2014 Background: The cyclin D-CDK4/6-Rb pathway is activated in most glioblastomas. Abemaciclib is a potent CDK4/6 inhibitor with good brain penetration approved for HR+/HER2- breast cancer. In order to efficiently evaluate the potential impact of abemaciclib on overall survival (OS) in newly diagnosed glioblastoma and to simultaneously develop information regarding potential genomic biomarker associations, abemaciclib was included as an arm on the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. INSIGhT is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and potentially accelerate identification of novel therapies for phase III testing. Initial randomization was equal between abemaciclib, control, and two other experimental arms but subsequent randomization was adapted based on efficacy as determined by progression-free survival (PFS). Ineffective arms were discontinued and new arms added by protocol amendment. We report preliminary results for the abemaciclib arm which has completed accrual. Methods: Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide at standard doses or standard radiochemotherapy followed by adjuvant abemaciclib (150-200 mg orally BID). Treatment continued until progression or development of unacceptable toxicities. The primary endpoint was OS which was assessed using the log-rank test estimated via the Kaplan Meier method using a type I error of 5%. The hazard ratio (HR) was estimated using a cox proportional hazards model. Association between abemaciclib efficacy and cyclin D-CDK4/6-Rb pathway genomic alterations was also investigated. Results: There were 142 patients (69 control; 73 treated with abemaciclib). Abemaciclib was generally well-tolerated with no new toxicity signals identified. PFS was significantly longer (HR 0.67; p = 0.03, logrank test) with abemaciclib (median 6.54 months) compared to the control arm (median 5.88 months). For patients with activation of the CDK4 pathway the PFS HR was 0.64 (p-value = 0.04). However, there was no significant improvement in overall survival (HR 0.9; p-value > 0.05) between abemaciclib (median 15.5) compared to the control arm (median 15.5). Conclusions: Abemaciclib was well-tolerated and prolonged PFS but there is no evidence of an overall survival improvement compared to standard radiochemotherapy. Clinical trial information: NCT02977780.

Background: Convection-enhanced delivery (CED) of therapeutic agents to brain tumors allows clinicians to bypass the blood-brain barrier (BBB) to infuse virus therapy, biological, or chemotherapy directly into a brain tumor through convection. However, the effectiveness of infusions via CED may depend on catheter placement. Methods: This study used diffusion maps from magnetic resonance imaging (MRI) of human brain tumors and computational fluid dynamics (CFD) simulations to assess therapy volume distribution percentages based on catheter placement locations. Results: The primary outcome showed differences in volume distribution based on the catheter placement location. Total tumor volume filled ranged from 144.40 mm3 to 317.98 mm3. Percent filled of tumor volume ranged from 2.87% to 6.32%. Conclusions: The selection of the location for catheter placement using the region with the highest volume filled may provide optimal therapeutic effect. The researchers conclude that CFD may provide guidance for catheter placement in CED of therapeutic agents.

BACKGROUND Disparities in healthcare delivery in the United States based on race and socioeconomic status are well-documented. Our study examined these disparities along with demographic differences in patients with gliomas. METHODS Data was collected retrospectively from an NCI Comprehensive Cancer Center between 2008–2020; 163 African-American patients and 1207 non-Hispanic white patients were included. Demographic variables were entered as predictors of tumor grade and type in an ANOVA model and multinomial logistic regression, respectively. A MANOVA model was used to assess differences in treatments received. Predictors of outcome were determined using cox regression. RESULTS Significant differences (p< 0.05) were found between African-American and non-Hispanic white patient groups in; age at diagnosis (48.68 vs 56.12 years, respectively), male/female gender ratio (0.75 vs 1.22), annual household income ($29,442 vs $40,028), insurance type (53.1% private and 42% public vs 63.4% private and 33.6% public) and marital status (43% married vs 74.1%). When controlling for these, there were no significant differences in tumor grade, type, MGMT methylation or IDH1 alteration statuses. Race alone did not predict treatment received, however, two-way interactions between race and other variables did. While gender differences in resection were small for non-Hispanic white controls, resection took place more often in African-American females than males (F = 4.779, p = 0.029). The deleterious effect of increased age on overall survival was diminished in African-Americans (B = -0.033, p < 0.001), while the effect of tumor grade was more pronounced (B = 0.595, p < 0.001). DISCUSSION This study suggests that disparities in outcomes are identified when race is considered within the context of other demographic, socioeconomic, and clinical factors. Moreover, these observations demonstrate the need for further studies into intersectional effects on treatment access and clinical outcomes, along with aggressive countermeasures to ensure equity of care.

Simple Summary Despite the numerous novel pharmacological and immunological approaches for multimodal glioma treatments that have been proposed in recent years, glioma phenotypic and genotypic spatial profiles in the course of treatments remain heterogeneous and, therefore, represent the biggest challenge for patient outcome. The elimination of glioma heterogeneity is an established chemotherapeutic goal. The role of the mRNA-binding protein of ELAV-family HuR in homotypic and heterotypic cell fusions via permanent intercellular membrane fusions and temporal intercellular tunneling nanotube formations in the glioma microenvironment leading to glioma heterogeneity will be discussed in our review with implications of HuR inhibitors in the prevention of these processes. Abstract Homotypic and heterotypic cell fusions via permanent membrane fusions and temporal tunneling nanotube formations in the glioma microenvironment were recently documented in vitro and in vivo and mediate glioma survival, plasticity, and recurrence. Chronic inflammation, a hypoxic environment, aberrant mitochondrial function, and ER stress due to unfolded protein accumulation upregulate cell fusion events, which leads to tumor heterogeneity and represents an adaptive mechanism to promote tumor cell survival and plasticity in cytotoxic, nutrient-deprived, mechanically stressed, and inflammatory microenvironments. Cell fusion is a multistep process, which consists of the activation of the cellular stress response, autophagy formation, rearrangement of cytoskeletal architecture in the areas of cell-to-cell contacts, and the expression of proinflammatory cytokines and fusogenic proteins. The mRNA-binding protein of ELAV-family HuR is a critical node, which orchestrates the stress response, autophagy formation, cytoskeletal architecture, and the expression of proinflammatory cytokines and fusogenic proteins. HuR is overexpressed in gliomas and is associated with poor prognosis and treatment resistance. Our review provides a link between the HuR role in the regulation of cell fusion and tunneling nanotube formations in the glioma microenvironment and the potential suppression of these processes by different classes of HuR inhibitors.

The purpose of this study is to determine the role of the complement immune system in glioma and/or glioma therapy. Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. It is accompanied by a devastating prognosis; the median survival is 12-14 months, with less than 10 percent of patients living for more than two years after diagnosis. Unfortunately, current treatment options are limited, and many initially promising drugs have failed phase three clinical trials. One potential and relatively unexplored target for co-therapy in GBM is the complement immune system. Historically, the focus of work with complement has been on its role in innate immunity, where it can aid in the recognition and elimination of pathogens or undesired host material. More recent work, however, has revealed a key function of complement as a “double-edged sword” in the CNS. While the cascade is necessary for CNS development and homeostasis, overactive complement can lead to the hallmark neuroinflammation and neurodegeneration seen in conditions like Alzheimer's, multiple sclerosis, and traumatic brain injuries. Yet despite the presence of complement receptors on nearly all CNS cells and the direct role that complement plays in multiple neuroinflammatory diseases, very few studies have examined complement expression in brain tumors. The current project seeks to bridge this gap in knowledge by assessing the impact of complement on glioma. This effort began by selecting candidate genes, as the complement family contains over 50 members. To do so, data from the publicly available Cancer Genome Atlas (TCGA) was mined, providing 14 targets of interest for further analysis. Cell-based experiments were performed in three GBM patient-derived xenolines (PDx): XD456, JX6, and JX10. mRNA expression was determined via TaqMan real-time PCR. Protein levels were assessed via Western blot. Overall, seven of the 14 initial targets demonstrated clear over-expression in all three human GBM PDx cell lines. This expression was not changed upon treatment with glioma growth factors such as epidermal or fibroblast growth factor (EGF or FGF). Intriguingly, however, the degree of over-expression varied by cell line, even when these lines were derived from patients assigned to the same molecular GBM subtype. For example, at the RNA level and in comparison to other cell lines, complement factor H (a C3 inhibitor) was up to six times higher in XD456, and clusterin (a MAC inhibitor) was nearly 18-fold higher in JX10. These data suggest that the current system for classifying tumor subtype may be missing important factors. Finally, when compared back to TCGA data, overexpression of these targets was associated with significantly worse tumor phenotype and patient survival. This project has critically identified components of the complement system that are upregulated in GBM and strongly correlated to survival. Ultimately, these data may provide the first potential targets for complement-based co-therapeutics to be explored in future studies. Citation Format: Emily Nicole Hayward, Xiuhua Yang, Natalia Filippova, Jennifer A. Calano, David Namkoong, Stefan Kovac, Louis B. Nabors. Characterization and analysis of the complement immune system in glioblastoma (GBM) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3335.

Importance One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders. Observations National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings. Conclusions and Relevance NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.

TPS3150 Background: Temozolomide (TMZ) transiently upregulates GBM-specific stress-induced NKG2D ligands that are targeted by innate immune effector cells. Leveraging this effect is problematic, however, due to the lymphodepleting effects of TMZ.Genetic modification of ex vivo expanded and activated with an MGMT-expressing lentivector allows simultaneous chemotherapy and γδ T cell therapy that targets the tumor when NKG2DL are maximally expressed. We have termed this Drug Resistant Immunotherapy (DRI). Patient-derived xenograft mouse models of both primary and recurrent GBM treated with DRI have shown a significant survival advantage that were otherwise impervious to either cell therapy or TMZ. These preclinical findings and associated safety data provide the rationale to initiate a Phase I trial of DRI in primary GBM. Methods: This first in human study will evaluate the safety and optimal dosing frequency of the DRI with TMZ (NCT04165941).Eligibility criteria include the following: GBM eligible for resection, ≥18y, adequate organ and marrow function, and KPS≥70. Six to 12patients with newly diagnosed GBM are being enrolled in a 3 + 3 design into 1 of 2 fixed dose levels (DL) of DRI. Following tumor resection and immediately prior to induction chemo/radiotherapy, an apheresis product is collected and γδ T cells expanded in Zoledronic Acid (Novartis) and rhIL-12 (Miltenyi) and transduced with a P140K-MGMT lentivector (Miltenyi Lentigen, Gaithersburg, MD), harvested, and cryopreserved. At initiation of maintenance phase TMZ therapy, patients receive 150mg/m2 intravenous TMZ concurrently with intracranial injection of 1 x 107 γδ T cells (DL1) delivered through a Rickham reservoir previously inserted into the tumor cavity at resection. The patient then receives 4 daily doses of oral TMZ followed by 24d rest. Treatment cycles escalate from 1 to 3 (DL2) DRI doses following a safety observation period and absence of dose limiting toxicity. Maintenance TMZ treatment will continue for 6 cycles. Safety evaluations consist of routine laboratory analyses, clinical measurements (physical exams, vital signs), neurological function and evidence DRI γδ T cell related toxicity. Peripheral blood will be obtained for comprehensive immuno-phenotyping and T cell function analysis. Clinical benefit of DRI will be characterized by evaluating responses (CR, PR, SD and PD) and determining progression-free, median, and overall survival. As of February 2020, enrollment into DL 1 is ongoing. Clinical trial information: NCT04165941 .

Methylmercury (MeHg) is an environmental neurotoxin with human exposure mainly from dietary intake of contaminated fish. Exposure to MeHg has been implicated in neurological damage, but research on its role in cancers, specifically glioma, is limited. In a glioma case-control study, we examined associations between toenail mercury (Hg) and glioma risk. We also examined genetic polymorphisms in 13 genes related to MeHg metabolism for association with glioma risk; genetic associations were also studied in the UK Biobank cohort. Median toenail Hg in cases and controls, respectively, was 0.066 μg/g and 0.069 μg/g (interquartile range (IQR): 0.032–0.161 and 0.031–0.150 μg/g). Toenail Hg was not found to be significantly associated with glioma risk (Odds Ratio: 1.02; 95% Confidence Interval: 0.91, 1.14; p = 0.70 in analysis for ordinal trend with increasing quartile of toenail MeHg). No genetic variant was statistically significant in both of the studies; one variant, rs11859163 (MMP2) had a combined p-value of 0.02 though it was no longer significant after adjustment for multiple testing (Bonferroni corrected p = 1). This study does not support the hypothesis that exposure to MeHg plays a role in the development of glioma at levels of exposure found in this study population.

BACKGROUND: To test the hypothesis that, despite bleeding risk, anticoagulants improve outcome in glioblastoma because of reduced incidence of venous thromboembolic events and modulation of angiogenesis, infiltration and invasion. MATERIAL AND METHODS: We assessed survival associations of anticoagulant use from baseline up to start of temozolomide chemoradiotherapy (TMZ/RT) (period I) and from there to the start of maintenance TMZ chemotherapy (period II) by pooling data of three randomized clinical trials in newly diagnosed glioblastoma including 1,273 patients. Progression-free survival (PFS) and overall survival (OS) were compared between patients with: anticoagulant use versus no use; therapeutic versus prophylactic versus no use; different durations of anticoagulant use versus no use; anticoagulant use versus use of anti-platelet agents, versus neither nor. Cox regression models were stratified by trial and adjusted for baseline prognostic factors. RESULTS: Anticoagulant use was documented in 75 patients (5.9%) in period I and in 104 patients (10.2%) in period II. Anticoagulant use during period II, but not period I, was associated with inferior OS compared to no use on multivariate analysis (p=0.001, HR=1.52, 95% CI: 1.18–1.95). No decrease in OS became apparent when only patients with prophylactic anticoagulant use were considered. No survival association was established for anti-platelet agent use. CONCLUSION: Anticoagulant use was not associated with improved OS. Anticoagulants may not exert relevant anti-tumor properties in glioblastoma.