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Background Outpatient clinics treating neuro-oncology patients are becoming more multidisciplinary. Utilization of all team members is critical for the holistic care of these complex patients. Specifically, the role of clinical pharmacist (CP) in the ambulatory clinic remains undefined and will likely evolve as more therapeutics are developed for CNS malignancies. We queried the Society for Neuro-Oncology (SNO) membership about the availability of a CP in their ambulatory setting and, if present, the role of that CP. Methods In an IRB-exempt study, we surveyed the SNO community and analyzed responses to queries about CPs in the ambulatory setting. Results Of the 65 SNO members who responded, 52 were clinical members. Of these 52 clinicians, the majority were physicians (88.5%, n = 46). Of these physicians, most were in academic practices (93.5%, n = 43). Over half of the 52 clinical respondents (51.9%, n = 27) reported that they saw ≥30 primary brain tumor patients per month, thus typifying busy clinics. Despite having busy clinics, only 12 (28.6%) of 42 providers with access to a CP reported that their CP was solely dedicated to neuro-oncology patients. For the respondents who had access to a CP, only ~two-thirds of those CPs had direct patient interaction. The top 3 roles of the CP included medication review, chemotherapy dosing/modifications, and practice guideline development; none of which involve direct patient interaction. Conclusions We found that while our surveyed population of SNO clinical members have demanding outpatient practices, most do not have the support or expertise of dedicated neuro-oncology CPs.

BACKGROUND Low grade gliomas (LGGs) develop in young adults and represent 10-15% of all glial tumors. While LGG patients can have longer survival than higher grade tumors, progression, transformation, and ultimately mortality occurs. Mutations in Isocitrate dehydrogenase 1/2 (IDH1/IDH2) are prevalent in LGG and are responsible for gliomagenesis. The classic IDH1 mutation is located at 132 codon and represented as p.Arg132His, but there are non-canonical IDH1 and IDH2 mutations. We sought to compare clinical characteristics of LGG patients with classic IDH1 p.Arg132His mutation to LGG patients with non-canonical IDH1 and IDH2 mutations. METHODS We queried an IRB-approved registry retrospectively from 12/2004- 9/2019. We included IDH1/IDH2 mutant LGG (WHO grade II) and known IDH1 and IDH2 targeted mutation analysis using standard PCR followed by DNA sequencing to detect point mutations in IDH1/IDH2 genes. We obtained available clinical and histopathological data. We estimated progression-free survival (PFS), time to transformation (TT), and overall survival (OS) using Kaplan-Meier methods. RESULTS We identified 267 LGG patients with median follow-up of 9.1 yrs (95%CI 8.4-9.9 yrs). Classic IDH1 p.Arg132His mutation occurred in 223 (83.9%) patients. IDH2 mutations occurred in 14 (5.2%) patients. Non-canonical IDH1 mutations were in 30 (11.2%) patients and included the following mutations: p.Arg132Cys (13), p.Arg132Gly (10), p.Arg132Ser (4), p.Arg132Leu (1), p.Arg119Gln (1), and p.Arg172Met (1). Initial presentation, OS, and TT did not differ between IDH1/IDH2 groups. PFS differed significantly between groups with improved median PFS in IDH2 mutant LGG (5.4 yrs; 95%CI 3.5-25.2) versus classic IDH1 mutant LGG (4.1 yrs; 95%CI 3.7-4.9 yrs) and non-canonical IDH1 mutant LGG (2.6 yrs; 95%CI 2.1-4.8) (log-rank p=0.019). Notably, non-canonical mutations were more common in astrocytoma (22/30; 73.3%) than other LGG histologies (p=0.018). CONCLUSIONS In this cohort, LGG patients with non-canonical mutations have a shorter time to progression than patients with classic p.Arg132His mutation and IDH2 mutations.

INTRODUCTION We previously reported to SNO, high levels of psychosocial distress in adult patients with primary brain tumors (PBTs), particularly during the first 6 months following diagnosis. The purpose of this follow-up study was to identify patterns of distress among older (≥ 65 years) patients with glioblastoma (GBM) compared to their younger (ages 18-64) counterparts. METHODS In our initial cross-sectional study, we collected the National Comprehensive Cancer Network’s Distress Thermometer (NCCN-DT) and problem list from adult patients with PBTs (WHO grades I-IV) seen at our institution between December 2013 and February 2016. We performed subsequent analyses on a subset of patients with GBM. RESULTS We identified 343 patients with GBM from the original dataset, of which 23.0% (n= 78) were ≥ 65 years old. The proportion of patients ≥ 65 years old with elevated distress (i.e. DT ≥ 4) was greater than the proportion of younger patients reporting elevated distress (47.4% vs 30.6%; p= 0.0068). Elevated distress was significantly greater during the first 6 months post diagnosis for all ages (p= 0.008). In subgroup analyses, a decrease in distress beyond 6 months was seen in younger patients (45.7% vs 27.4%; p= 0.021), but not in older patients. In older patients, a greater number of problems were selected on the NCCN DT and problem list tool: emotional and physical concerns were reported more frequently compared to their younger counterparts. Older patients were more likely to report difficulty with “bathing” and “getting around” (p= 0.009, p< 0.001, respectively). There were no differences in older versus younger GBM patients with regard to housing, transportation, treatment decisions, depression, fatigue, or memory. CONCLUSIONS In contrast to their younger counterparts, older patients with GBM experienced elevated levels of distress and a greater absolute number of specific psychosocial problems, mostly related to emotional and physical concerns.

Background In patients with isolated HER2+ BrCBM and no extracranial disease (ECD), there are no consensus guidelines on optimal treatment approaches following CNS-directed therapy. Our goal was to determine the implications of ECD at time of first HER2+ BrCBM on intracranial progression-free survival (PFS1) and overall survival (OS). Methods Retrospective analysis was performed on 77 patients with HER2+ BrCBM who received 1st CNS radiation from 2006–2020. Demographics, dates of metastatic and intracranial diagnosis, ECD status at 1st BrCBM, and outcomes were collected. The primary endpoint was PFS1 defined as time from first CNS radiation to the subsequent documentation of intracranial progression (RANO-BM). OS was defined as time from 1st CNS radiation and 1st metastatic disease to date of death/last known alive. ECD status was defined by RECIST1.1 from staging scans within 30 days of 1st BrCBM. Results In this patient cohort, 25% (19/77) had isolated brain relapse/no ECD. Median age was 50 years. Most patients (58%) developed first BrCBM during adjuvant or early-line metastatic therapy. All patients with no ECD presented with isolated brain relapse as first metastatic presentation. Patients with concurrent ECD presented with first BrCBM at a median of 16.6m (95% CI: 10.5 to 25.3) after initial metastatic presentation. Median OS from initial metastatic presentation to death was worse for patients with isolated brain relapse (25.3m, 95% CI: 16.8 to 35.3) compared to those with concurrent ECD (49.7m, 95% CI: 43.2 to 62; p=0.01). Median OS from first CNS involvement to death was not statistically different amongst groups. Conclusions Patients with isolated HER2+ BrCBM as their initial metastatic event have substantially worse OS compared to patients with concurrent ECD developing CNS metastases later in their disease course. This population with isolated brain relapse deserves investigation of novel treatment algorithms, including earlier introduction of brain-penetrable HER2-targeted agents.

OBJECTIVE There is no validated model for delivering palliative care (PC) in the glioblastoma (GBM) population. The primary objectives were to assess the feasibility and determine the acceptability of a time-based model of integrated specialty PC to patients and providers. Secondary objectives were to estimate the impact on healthcare utilization and quality of life (QoL) compared to historical controls. METHODS We consented and referred patients to PC at their initial Neuro-Oncology consultation between 4/2018 and 5/2019. We conducted QoL assessments (NCCN Distress Tool; Functional Assessment of Cancer Therapy-Brain (FACT-BR); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); Epworth Sleepiness Scale (ESS)) at (1) baseline (2) immediately after chemoradiation, and (3) 6 months following chemoradiation. Ongoing PC follow-up was at the discretion of the PC provider. We administered the Edmonton Symptom Assessment System (ESAS) before and after PC visits. We measured patient and referring provider satisfaction using FAMCARE-16 and a PC departmental survey, respectively. RESULTS We did not meet our goal enrollment of 50 patients. 32 were offered participation, 12 consented and 8 attended at least one PC visit. The mean number of PC visits was 1.6. Mean age was 62 (42–79). 75% had a KPS ≥80. Of those that did not complete the study, 2 died and 5 either withdrew consent or declined further visits. At baseline, 91.7 % had a NCCN distress score ≥4. Patients were overall satisfied with the intervention. CONCLUSION Introduction of specialty PC at the time of GBM diagnosis is challenging. Participants reported their experience as overall positive. Results from referring providers are pending. Due to low-enrollment we did not pursue further statistical comparisons regarding healthcare utilization compared to historical controls.

BACKGROUND Outpatient clinics treating neuro-oncology patients are becoming more multidisciplinary. Utilization of all team members is critical for the holistic care of these complex patients. Specifically, the role of a clinical pharmacist in the ambulatory multidisciplinary clinic remains undefined and will likely evolve as more therapeutic options are developed to treat central nervous system malignancies. We queried the Society for Neuro-Oncology (SNO) membership about the availability of a clinical pharmacist in their ambulatory setting and, if present, the role of that clinical pharmacist. METHODS In an IRB exempt study, we surveyed the SNO community (targeting primarily clinicians) and analyzed responses to queries about clinical pharmacists in the ambulatory neuro-oncology setting. RESULTS Of the 65 SNO members who responded, 52 of these were clinical members. Of these 52 clinical members, the majority were physicians (88.5%, n=46). Of these 46 physicians, most were in academic practices (93.5%, n=43). Over half of the 52 clinical respondents (51.9%, n=27) reported that they saw ≥ 30 primary brain tumor patients a month, thus typifying busy clinical neuro-oncology ambulatory clinics. Despite having busy clinics, only 12 (28.6%) of the 42 providers with access to a clinical pharmacist reported that their clinical pharmacist was solely dedicated to neuro-oncology patients. For the respondents who had access to a clinical pharmacist, only 28 (66.7%) of those pharmacists had direct patient interaction in the clinic. The top three roles of the clinical pharmacist included medication review (81%, n=34), chemotherapy dosing and modifications (73.8%, n=31), and practice guideline development (61.9%, n=26), none of which are associated with direct patient interaction. CONCLUSIONS We found that while our surveyed population of SNO clinical members have demanding outpatient neuro-oncology practices, most do not have the support or expertise of dedicated neuro-oncology clinical pharmacists.

BACKGROUND Low grade gliomas (LGGs) represent 10–15% of glial tumors in adults and while LGG patients have a better prognosis over high-grade gliomas, these cancers ultimately recur and transform to more aggressive tumors. Isocitrate dehydrogenase 1 (IDH1) is commonly mutated in LGG, and when mutated, it is the oncogenic driver by leading to the production of oncometabolite 2-hydroxyglutarate (2-HG). We developed a phase 1 study for recurrent resectable IDH1 mutant LGG utilizing a tumor-specific peptide vaccine targeting IDH1 mutant protein that spans the mutated region of IDHR132H (PEPIDH1M vaccine). METHODS We performed a phase 1, single-center, clinical trial in recurrent resectable IDH1 mutant WHO grade II glioma patients. Subjects received three PEPIDH1M vaccine q2wks and then proceeded to surgical resection. If subject’s tumor retained grade II status, then the subject proceeded with 12 cycles of daily TMZ (50 mg/m2 X 28 days) and PEPIDH1M vaccine (12 injections q4wks). If subject’s tumor transformed to grade III, then subject proceeded to radiation therapy (RT) with concurrent TMZ followed by 12 cycles of daily TMZ (50 mg/m2 X 28 days) and PEPIDH1M vaccine (12 injections q4wks). Primary endpoint was safety of PEPIDH1M vaccine in combination with adjuvant TMZ and/or XRT/TMZ and evaluable subjects needed to receive ≥6 PEPIDH1M vaccines. We assessed safety using CTCAE 4.03. RESULTS We enrolled 24 recurrent LGG subjects with mean age of 43.8 yrs (sd=11.4 yrs). Twenty subjects completed ≥6 PEPIDH1M vaccines. Most common related toxicity was grade 1 injection site reaction (N=20) and skin induration (n=17) with no grade 3–4 related toxicities. CONCLUSIONS PEPIDH1M vaccine in combination with surgical resection, daily TMZ and/or RT + TMZ with daily TMZ was safe and well tolerated in recurrent IDH1 mutant LGG. We are currently exploring secondary/correlative endpoints including immunogenicity of PEPIDH1M vaccine and magnetic resonance spectroscopy for 2-HG.

BACKGROUND The live attenuated oral poliovirus vaccine was modified to contain a heterologous internal ribosomal entry site stemming from human rhinovirus type 2, creating PVSRIPO. PVSRIPO recognizes CD155, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. We have previously reported that deep sequencing of biopsy material obtained prior to PVSRIPO infusion confirmed that a very low mutational load is associated with longer survival. METHODS Patient tumor material from both phase I and 2 clinical trials was collected pre PVSRIPO. When available, post-treatment tissue from longitudinal samples were also collected. Tissue was subjected to RNA sequencing, histological analysis, and flow cytometry analysis. RNAseq analyses were performed comparing pre- and post- treatment expression profiles and computational predictions of tumor immune composition deciphered changes after PVSRIPO therapy. Histology and flow cytometry quantitated myeloid, CD8/4/regulatory T cell densities, and other immune cell types after treatment and compared to baseline tissue similarly analyzed to detect changes. RESULTS To date, analysis of phase 1 trial data has demonstrated a correlation between low TMB and increased markers of immunological gene expression profiles. This trend was not observed in TCGA samples that were almost exclusively primary GBM suggesting and interplay with prior therapy or evolution with recurrence. CONCLUSION Our findings presented here suggest that response to PVSRIPO therapy, and possibly that of other modalities engaging innate antiviral signatures in situ, may be dependent upon prevailing tumor microenvironment composition/status at the time of treatment.

We sought to identify characteristics of glioblastoma (GBM) patients with short survival (< 10 months) in order to identify prognostic factors useful for guiding treatment management. This is an IRB-approved retrospective analysis of adult newly diagnosed GBM patients from 2008–2016 who survived < 10 months from diagnosis. We extracted demographics, tumor characteristics, and treatment details. We calculated survival from surgical diagnosis to date of death. The cohort includes 197 subjects (61% male) with a median age of 68 years (range 19–94). The majority (93%) are non-Hispanic white. The cohort has a median survival of 144 days (95% CI: 130–160). We focused on traditional prognostic indicators, including extent of surgical resection and KPS. A majority had biopsy only (n=92, 46.7%) rather than gross total (n=59, 29.9%) or subtotal (n=46, 23.4%) resection. Moreover, 160 out of 197 patients had a documented KPS with a majority being below 90 (KPS=70–80 (n=96); KPS < 70 (n=31)). Of 179 patients with data on RT course, 18% (n=32) received no RT or opted for hospice after diagnosis, 3% (n=6) received only RT, 54% (n=97) received RT+temozolomide (TMZ), and 24% (n=43) received RT+TMZ+bevacizumab. Of the 147 subjects receiving RT, 79% completed their RT course as prescribed. Most commonly, RT was prescribed as a 6- to 6-1/2-week course (85%), typically 59.4 Gy (45Gy primary, 14.4Gy boost) over 33 fractions or 60 Gy over 30 fractions. In contrast, 15% received a 3-week RT course, typically scheduled as 15 fractions of 2.667 Gy. We concluded that GBM patients with survival < 10 months were more likely to have biopsy only and a KPS < 90, notably associated with poorer prognosis. We continue to explore this dataset for further prognostic factors, particularly inability to complete planned RT course, and are comparing these traits to a larger cohort.

With a bleak prognosis for malignant glioma, maintaining quality of life (QoL) and decreasing distress of the patient are important in the clinical care of the patient. Mindfulness meditation is a mind-body therapy that has been recently investigated in the oncology field as a non-pharmacological strategy to ameliorate cancer symptoms and to improve QoL. This practice has not been studied in the primary brain tumor population. We initiated a pilot study among newly diagnosed brain tumor patients with the hypothesis that mindfulness meditation practice may benefit the patient by decreasing stress and anxiety and provide a means to cope with their new diagnosis. The specific aim of this pilot study is to determine the feasibility of a mindfulness meditation program to this population during standard of care chemoradiation and to determine whether it merits additional research in a subsequent trial. The intervention consists of six weekly one hour telephone-based mindfulness sessions followed by one in- person mindfulness session consisting of: mindfulness and healing, understanding stress, abiding in kindness, working with difficult emotions, finding peace, going forward and living fully. Subjects are provided with downloadable guided meditations. We plan to enroll fifteen newly diagnosed WHO grade III or IV malignant glioma subjects prior to their 6 week chemoradiation course. We will determine the percentage of subjects approached vs enrolled, number of sessions that each subject attends, completion of study questionnaires and satisfaction of the subjects. QoL surveys include: Functional Assessment of Cancer Therapy- Brain, Functional Assessment of Cancer Therapy- Cognitive Function, Pittsburgh Sleep Quality Index, Functional Assessment of Chronic Illness Therapy-Fatigue and the Five Facet Mindfulness Questionnaire – short form. 13 subjects have been approached and 8 signed consent over a two-month period. We will provide final study results at time of presentation.

BACKGROUND: An impermeable blood–brain barrier and drug efflux via ATP-binding cassette (ABC) transporters such as p-glycoprotein may contribute to underwhelming efficacy of peripherally delivered agents to treat diffuse intrinsic pontine glioma (DIPG). OBJECTIVE: To explore the pharmacological augmentation of convection-enhanced delivery (CED) infusate for DIPG. METHODS: The efficacy of CED dasatinib, a tyrosine kinase inhibitor, in a transgenic H3.3K27M mutant murine model was assessed. mRNA expression of ABCB1 (p-glycoprotein) was analyzed in 14 tumor types in 274 children. In Vitro viability studies of dasatinib, the p-glycoprotein inhibitor, tariquidar, and dexamethasone were performed in 2 H3.3K27M mutant cell lines. Magnetic resonance imaging (MRI) was used to evaluate CED infusate (gadolinium/dasatinib) distribution in animals pretreated with tariquidar and dexamethasone. Histological assessment of apoptosis was performed. RESULTS: Continuous delivery CED dasatinib improved median overall survival (OS) of animals harboring DIPG in comparison to vehicle (39.5 and 28.5 d, respectively; P = .0139). Mean ABCB1 expression was highest in K27M gliomas. In Vitro, the addition of tariquidar and dexamethasone further enhanced the efficacy of dasatinib (P

BACKGROUND Recurrent medulloblastoma and malignant glioma are lethal tumors that are virtually incurable. The cytomegalovirus (CMV) antigen pp65 is ubiquitously expressed on medulloblastoma and malignant glioma but not on healthy brain. We evaluated autologous CMV pp65 RNA-pulsed dendritic cell (DC) vaccines in children and young adults in a phase I trial. METHODS Circulating monocytes were harvested using leukapheresis, differentiated into DCs, matured, and pulsed with pp65 RNA using electroporation. DCs were packaged into vaccines (2x107DC/vaccine) and administered intradermally following tetanus-diphtheria toxoid site preconditioning every 2 weeks x3, then monthly. The primary objectives of the study were to establish the feasibility of generating at least 3 vaccines and safety. An exploratory objective was to evaluate the ability of vaccination to create and enhance patient pp65-specific T cell responses. RESULTS Eleven patients were enrolled with medulloblastoma (n=3) or glioblastoma (n=8). Ages ranged from 9–30 years old (mean 15.5y). Ten of 11 patients (91%) generated at least 3 vaccines (mean 6.2). Eight patients received at least 3 vaccines. To date, 4 patients have received all generated vaccines without progression, 4 patients have progressed, and 2 patients are still receiving vaccines. There have not been any severe adverse events probably or definitely related to vaccines. More mature data will be presented at ISPNO. CONCLUSIONS Leukapheresis and monocyte differentiation is a feasible strategy for generating adequate DCs for active immunization in children with malignant brain tumors. CMV pp65 RNA-pulsed DCs are well-tolerated and immunogenic. Efficacy endpoints will be evaluated in a subsequent phase II trial.

Glioma therapeutic resistance to alkylating chemotherapy is mediated via O6-methylguanine-DNA methyltransferase (MGMT). We hypothesized that a CD45/HAM56/MGMT double-stained cocktail would improve MGMT discrimination in tumor cells versus inflammatory and endothelial cells (IEC). Total MGMT protein was quantified by IHC on 982 glioblastomas (GBM) and 199 anaplastic astrocytomas. Correcting for IEC was done by a CD45/HAM56/MGMT 2-color cocktail. Lowest IEC infiltrates (IEC “cold spots”) were identified to quantitate MGMT as well as the percentage of IEC% in the IEC cold spots. MGMT promoter methylation (PM) was also determined. Among the GBM biopsies, mean uncorrected and corrected MGMT% were 19.87 (range 0–90) and 16.67; mean IEC% was 18.65 (range 1–80). Four hundred and fifty one (45.9%) GBM biopsies were positive MGMT PM. Both uncorrected and corrected MGMT% positivity correlated with PM. All 3 MGMT scores correlated with overall survival (OS) in GBM’s. Cold spot IEC% was also positively associated with OS. These effects remained in a multivariate model after adjusting for age and disease status. Prognosis determined by correcting MGMT% score for IEC% is not improved in this analysis. However, IEC COLD SPOT score does provide additional prognostic information that can be gained from this correction method.

INTRODUCTION: Meningiomas, the most common CNS neoplasm, are often deemed less threatening than their glial counterparts. Unfortunately, these tumors recur and necessitate surgery, radiation, and/or systemic treatment. We explored the psychosocial distress of patients with recurrent meningioma using The National Comprehensive Cancer Network Distress Thermometer (NCCN-DT) and Problem List. METHODS: This was a retrospective analysis of patients with recurrent meningioma seen at the Preston Robert Tisch Brain Tumor Center between 12/31/2004–10/10/2018 who completed a NCCN-DT and Problem List. The first or only NCCN-DT assessment after initial recurrence was used for analysis with a score of 4 indicating moderate to severe distress. RESULTS: 45 patients were identified, 56% female, median age was 61 years and 58% had unifocal disease. 60% were Grade 1, 33% Grade II, 4% Grade III, and 2% indeterminate recurrent meningioma. The median NCCN-DT score was 3, and 49% had a NCCN-DT score 4 indicating moderate to severe distress. 64% of females vs 30% of males reported distress scores 4 (p=0.04). 65% of patients with unifocal disease reported 4 scores compared to 26% with multifocal disease (p=0.02). Fatigue (N=24), Worry (N=23), Nervousness (N=22), Depression (N=19) and Memory/Concentration (N=19) were the most commonly reported problems. A higher incidence of worry among females (64%) than males (35%) was the only problem showing a trend towards significance (p=0.08). Between initial recurrence and NCCN assessment, the type and number of treatments patients received included: surgery (median=1, range 0–5), radiation (median=2, range 0–5), systemic treatment (median=2, range 0–12). There was no association between distress and the number of surgeries (p=0.99), radiation treatments (p=0.49) or systemic therapies (p=0.87). CONCLUSIONS: In our study population, nearly half of recurrent meningioma patients reported moderate to severe distress. Therefore, even in this benign tumor population, the NCCN-DT and problem list should be administered at every clinic visit.

BACKGROUND: D2C7-IT is a recombinant immunotoxin comprised of a dual-specific antibody fragment targeting EGFRwt and EGFRvIII and a genetically engineered form of the Pseudomonas exotoxin, PE38-KDEL. We report results of a phase 1 trial evaluating D2C7-IT delivered intratumorally by CED. METHODS: Eligible patients are adults with recurrent supratentorial WHO grade III or IV MG; solitary tumor; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS>70%. Planned enrollment of two patients per dose level (DL). RESULTS: As of 5/29/2018, 43 patients have been treated (2 each per DL, but for DLs 3, 6, 9, and 16). Observed dose limiting toxicities include: grade 4 seizure (n=1) on DL3, grade 3 confusion and pyramidal tract syndrome (n=1) on DL13, and grade 4 cerebral edema and grade 3 dysphasia (n=2) on DL17. Grade 2 or higher adverse events possibly related to D2C7-IT include: seizure (grade 4, n=2, grade 3, n=2, grade 2, n=4), cerebral edema (grade 4, n=1), headache (grade 3, n=4; grade 2, n=18), hemiparesis (grade 3, n=4, grade 2, n=10), dysphasia (grade 3, n=2; grade 2, n=9), confusion (grade 3, n=1; grade 2, n=5), thromboembolic event (grade 3, n=2; grade 2, n=1), fatigue (grade 2, n=6), visual field cut (grade 2, n=3), paresthesia (grade 2, n=2), stroke (grade 2, n=2), and hemineglect (grade 2, n=2); one each of grade 3 elevated ALT, urinary tract infection, fall, generalized muscle weakness, encephalopathy, and somnolence; one each of grade 2 elevated AST, papilledema, gait disturbance, intracranial hemorrhage, and urinary incontinence. Fifteen patients are alive. Two patients have partial response and are alive ≥8.2 months and ≥34 months after infusion. CONCLUSION: DL17 is above the maximal tolerated dose. Encouraging efficacy results were observed. After review of efficacy and safety data, DL13 seems the optimal dose, additional patients will be treated on DL13.

Two of our previous clinical trials targeting Cytomegalovirus (CMV) protein pp65 in newly diagnosed glioblastoma (GBM) using pp65-specific dendritic cell (DC) vaccines have yielded long term survival rates greatly exceeding those predicted with standard of care. In the ATTAC trial (IND 12839), patients received sequential DC vaccination throughout monthly cycles of standard temozolomide (STD-TMZ) 200mg/m(2)/d for 5d and were randomized to one of two vaccine site preconditioning regimens. Significantly higher rates of DC migration (p=0.04) and survival (p=0.013) were observed in patients randomized to tetanus preconditioning, with half of the cohort living to nearly five years after diagnosis. In the ATTAC-GM trial, we treated a subsequent cohort with dose-intensified TMZ (DI-TMZ) 100mg/m(2)/d for 21d prior to and throughout vaccination with GM-CSF-containing DC vaccines and observed extraordinarily prolonged progression-free survival (PFS) and overall survival (OS) (median 25.3 and 41.1 months, respectively). In this trial, DI-TMZ-induced lymphopenia facilitated homeostatic expansion of pp65 responses after an initial DI-TMZ cycle but later ablated T cell responses when monthly cycles were reintroduced. The benefit of DI-TMZ thus warrants further study in a larger series of patients. Here we describe the initiation of a validation trial, “I-ATTAC: Improved Anti-Tumor Immunotherapy Targeted Against Cytomegalovirus in Patients with Newly-Diagnosed WHO Grade IV Unmethylated Glioma” (IND-16301). This prospective single arm Phase 2 trial of 48 patients will validate our findings that tetanus preconditioning and GM-CSF in conjunction with pp65-DCs extends OS in patients with newly diagnosed, unmethylated GBM. By withholding additional TMZ cycles in this patient population, we hypothesize that CMV immune responses will not be abrogated as previously observed, and that this greater expansion will translate into further prolonged survival (primary objective). A series of secondary objectives will be evaluated for the association between increased DC migration, systemic mediators of tetanus preconditioning, and T cell polyfunctionality with survival.

We performed a phase I study to assess feasibility, safety, and efficacy of ALT+DCV following HDC +ASCR (group A) or NMAC (group B) in pts with r-PNET. METHODS: Eligible pts underwent surgery to confirm diagnosis and obtain tumor for vaccine preparation. Pts with local (group A) or metastatic (group B) recurrence received 4 cycles of cytoreductive chemotherapy prior to either MAC (carboplatin + thiotepa + etoposide) (group A) or NMAC (cyclophosphamide + Fludarabine) (group B). Two dose levels of ALT were evaluated [3 x 10(6) or 3 x 10(7) cells/kg] with 3 intradermal biweekly DCVs (10(7)cells each). Safety evaluation for DLT assessment was 2 weeks past third DCV with monthly vaccines thereafter as available. Correlative studies for immune response included TCR sequencing and measurement of serum cytokines RESULTS: Ten pts (M5; F5) were treated on protocol (group A 1, group B 9). Nine evaluable pts received immunotherapy; DCV [median 3 doses (3-9)] + ALT [3 x10(6)/kg (n=4) or 3 x 10(7)/kg (n=5)]. There were no DLTs observed. At median of 21 months follow-up, 3 pts are alive with (n=2) or without (n=1) disease 33-42 months following treatment. TCR RNA sequencing demonstrates massive clonal expansion of T cells following ALT+DCV and positive correlation with clinical outcomes. Persistence of tumor-reactive (IFN-gamma secreting) T cell clones in the peripheral blood was observed 4 months after treatment in a patient with long-term disease control. CONCLUSIONS: ALT+DCV is feasible, safe, and shows signs of biologic and clinical activity in some pts with r-PNET.

BACKGROUND: Prognosis of recurrent World Health Organization (WHO) grade IV malignant glioma (GBM) in children is dismal with no effective therapy. We have recently performed a dose-finding and toxicity study within adults with GBM, evaluating the recombinant non-pathogenic polio/rhinovirus chimera (PVSRIPO) by intratumoral convection-enhanced delivery (CED). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of tumor stroma. We have commenced a Phase Ib study to evaluate feasibility, safety, and preliminary evidence of efficacy of the optimal adult dose in a pediatric population. METHODS: Patients with a recurrent supratentorial WHO Grade III malignant glioma (anaplastic astrocytoma, anaplastic oligoastrocytoma, anaplastic oligodendroglioma, anaplastic pleomorphic xanthoastrocytoma, ependymoma) or WHO Grade IV malignant glioma (glioblastoma, gliosarcoma) based on imaging studies with measurable disease (≥ 1 cm and ≤ 5.5 cm of contrast-enhancing tumor) will be enrolled. A stereotactic biopsy will be performed prior to virus administration. Immediately following the stereotactically-guided tumor biopsy, a catheter will be implanted in the operating room. PVSRIPO will then be delivered intratumorally by CED, using the catheter placed within the enhancing portion of the tumor, at a dose of 5 x 10(7) TCID over 6.5 hours. CONCLUSION: We will confirm the activity of intratumoral PVSRIPO infusion in recurrent WHO grade III or IV malignant glioma in the absence of neurovirulent potential in children.

Nearly one-third of patients with primary brain tumors experience a seizure as the presenting symptom and another 30-50% develop seizures during the disease course. Despite a wide availability of anti-seizure medications, some brain tumor patients have treatment refractory seizures. Perampanel is a highly selective non-competitive-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type glutamate receptor antagonist that is approved as an adjunct for partial-onset and primary generalized tonic-clonic seizures. We conducted a single-arm study to assess the safety, tolerability and efficacy of perampanel as an adjunctive anti-epileptic drug in patients with gliomas who have refractory partial-onset seizures. Participants were treated with a dose escalation of perampanel: 2 mg/day for two weeks, followed by 2mg-weekly increments up to a maximal dose of 8mg/day and then continued at this dose for 12 weeks. After 16 weeks of therapy, perampanel was tapered down by 2mg/week until the patients were no longer taking perampanel. Assessments included evaluations of Karnofsky Performance Status, seizure history, patient-reported outcomes of quality of life, and computer-based neurocognitive testing. Eight subjects were treated on study. Glioma subtypes represented: glioblastoma (n=1), anaplastic astrocytoma (n=3), anaplastic oligodendroglioma (n=1), oligodendroglioma (n=2) and diffuse astrocytoma (n=1). Seizure frequency varied widely between subjects. Three participants had clear reductions in seizure frequency after treatment initiation. The most common adverse events related to perampanel were fatigue (n=5) and dizziness (n=2). One participant died 8 weeks after study enrollment secondary to Pneumocystis jiroveci pneumonia and was deemed to be unrelated to perampanel. Of note, the study was stopped due to poor accrual. Adjunctive perampanel for patients with glial brain tumors and refractory partial-onset seizures is safe. Overall, this study suggests that perampanel is effective for refractory epilepsy in the brain tumor population but a larger study is needed to address definitively this question.

Fatigue is one of the most common symptoms experienced by patients with GBM. Whether it is associated with disease or treatment, we have shown in previous studies that fatigue is an independent prognostic factor for survival, and more fatigue is associated with a poorer overall survival. The association between tumor progression and fatigue in newly diagnosed GBM patients was explored within a clinical study investigating the use of bevacizumab (BV) with concurrent chemoradiation, followed by BV and temozolomide with the continuation of BV following progression. In this prospective single-center study, fatigue was evaluated using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) at time of study enrollment (before chemoradiation), after chemoradiation, and then every 6 mos until study discontinuation or subject demise. Higher scores on the FACIT-F indicate less reported fatigue. 68 newly diagnosed GBM patients were enrolled with a mean age of 55.4 yrs (sd=10.7 yrs). KPS ranged 70-100 with the following distribution: 70 (n=4), 80 (n=28), 90 (n=34), and 100 (n=2). Subjects who continued study participation 6 mos after the completion of chemoradiation were divided into two groups: subjects with (n=15) and without (n=35) tumor progression 6 mos after chemoradiation completion. Both groups had similar FACIT-F scores at baseline (group with progression mean=38.33 (sd=10.91) and group without progression mean=38.48 (sd=9.30)). Fatigue increased in subjects that had tumor progression to mean=33.60 (sd=11.94) and remained relatively stable in subjects that did not progress with mean=39.05 (sd=9.77). These findings suggest that newly diagnosed GBM patients with similar levels of baseline fatigue will experience increased fatigue when tumor progression occurs. With the association of fatigue levels and survival, more research is needed to combat fatigue and deleterious effects of this symptom on morbidity and mortality in GBM patients.

BACKGROUND: Prognosis of recurrent MG remains poor with a median survival of 3-11 months for patients on BEV-containing regimens. Few active evidence-based treatments are available & response rates have been

BACKGROUND: PVSRIPO is the live attenuated, oral (SABIN) serotype 1 poliovirus vaccine containing a heterologous internal ribosomal entry site stemming from human rhinovirus type 2. PVSRIPO recognizes nectin-like molecule-5, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. We report results of a phase 1 trial evaluating PVSRIPO delivered intratumorally by convection-enhanced delivery (CED). METHODS: Eligible patients were adults with recurrent supratentorial GBM; solitary tumor 1-5cm in diameter; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; KPS > 70%; and positive anti-polio titer. The original two-step continual reassessment method dose escalation was amended to treat 6 patients at level 2 after observing prolonged steroid use in 5 of 7 patients treated on levels 3 to 5. RESULTS: Thus far, 13 patients have been treated (1 each levels 1 and 3, 5 level 2, 2 level 4, 4 level 5). One dose limiting toxicity was observed, grade 4 intracranial hemorrhage at catheter removal (level 5). Adverse events possibly related to study include: hemiparesis (grade 3, n = 3; grade 2, n = 1; grade 1, n = 1); lymphopenia (grade 3, n = 1); seizure (grade 3, n = 1; grade 2, n = 1; grade 1, n = 2); dysphasia (grade 2, n = 1; grade 1, n = 1); lethargy (grade 1, n = 4); headache (grade 2, n = 1; grade 1, n = 2); one each of grade 2 diarrhea, paresthesia and hyperbilirubinemia; and one each of grade 1 fever, cough, nasal congestion, memory impairment, thrombocytopenia, anemia, nausea and vomiting. Ten patients remain alive, with pts #1 and #2 now 25 and 24 months post-PVSRIPO, respectively. Patients on levels 3 to 5 requiring prolonged steroid use were initiated on bevacizumab, allowing tapering down steroids. CONCLUSION: Infusion of PVSRIPO via CED is safe thus far and encouraging efficacy results are observed. Enrollment will be completed for the meeting.

BACKGROUND: Despite aggressive surgery, high-dose focused radiation, and multimechanistic chemotherapy, malignant gliomas (MG) remain almost universally fatal. The inherent biologic specificity of immunotherapy offers the prospect of targeting neoplastic cells more precisely. Dendritic cells (DCs) are endowed with an extraordinary ability to activate CD4+ and CD8+ T-cells, and DCs loaded with antigens derived from tumor cells (CMV pp65-LAMP mRNA) have the potential to induce potent antitumor immunity. Furthermore, regulatory T-cells (TRegs) which induce a state of reversible immunosuppression in MG and can be functionally inactivated with anti-CD25 antibody (Ab), while dramatically enhance vaccine-induced immune responses. METHODS: Eligible were gross totally resected patients (pts) with newly diagnosed GBM. Pts underwent leukapheresis followed by standard of care radiation/temozolomide (XRT/TMZ) therapy. After completion of XRT/TMZ, up to 12 cycles of TMZ 200 mg/m2/x5d were administered. Around Day 21 of the 1st cycle pts also received: anti-CD25 Ab treatment and vaccine #1. Vaccines #2 and #3 were given biweekly following vaccine#1. On Day 21 of the 2nd TMZ cycle Vaccine #4 was administered. Pts were followed with serial MRIs until disease progression. RESULTS: 7 patients (5 males) were treated. No adverse events attributable to vaccine treatment were observed. Median progression free survival was 23.5 months (95% CI:1.7 to 54.1). Median overall survival was 30.3 months (95% CI:11.8 to 60.8). Overall survival was calculated from the start of vaccine therapy to time of death or last contact if alive. CONCLUSION: Treatment with XRT/TMZ, DC vaccine and anti- CD25 Ab was well tolerated and produced encouraging PFS and OS resulting in now ongoing Phase I study. Due to the lack of adverse events the number of vaccines had been increased to 8 (vs. 4) and anti-CD25 antibody is being given with the first two cycles (vs. with 1st cycle only) of adjuvant TMZ.

BACKGROUND: Two multicenter phase III trials, RTOG0825 and AVAglio, evaluated the addition of BEV to radiation and temozolomide in newly diagnosed GBM and demonstrated a lack of statistically significant increased survival and discordant health-related quality of life results. We performed a retrospective chart review in newly diagnosed GBM to understand clinical benefit in BEV-treated patients in the community. METHODS: Newly diagnosed adult GBM pts treated at Duke were identified through our "Primary and Recurrent Glioblastoma Registry". We conducted a retrospective chart review of pts who initiated BEV between 1/1/2009 and 5/14/2012. Pts who participated in a clinical trial prior to receiving BEV were excluded. Pts alive on 5/15/2012 consented to the prospective collection of their data. Demographic and clinical data, including corticosteroid use and Karnofsky performance status (KPS), were analyzed. OS, PFS and time to KPS reduction were measured from BEV initiation. RESULTS: A total of 188 pts have been analyzed. At BEV initiation, median age was 57 years, 64% were male, 86% had KPS ≥80, and 46% were on corticosteroids. Median OS was 23.3 months (95% CI, 20.0-26.2 months). Median PFS was 14.8 months (95%CI, 12.2-17.9 months). Median time to KPS reduction ≥10-points and ≥20-points were 10.8 and 34.0 months, respectively. Of 86 pts on steroids pre-BEV, 78% discontinued steroids at a median of 64 days. Of 102 pts not on steroids pre-BEV, 57% did not initiate steroids, 31% initiated steroids while on BEV, and 12% initiated steroids while on another regimen. CONCLUSION: In newly diagnosed GBM pts treated on BEV in clinical practice, this retrospective review suggests a median OS and median PFS of 23.3 and 14.8 months, respectively. A majority of patients discontinued steroids, or remained off steroids during BEV treatment. Initial KPS levels were maintained by 86% of pts through the first year of follow-up.

After diagnosis, glioblastoma (GBM) patients quickly experience the neurological, physical, and emotional impact of their disease. Even before chemoradiation treatment, health-related quality of life (HRQoL) can be impaired and fatigue can be present due to neurological dysfunction, co-morbidities (e.g. seizures, depression), and medications (e.g. corticosteroids, anti-epileptics). We evaluated the impact of HRQoL and fatigue on survival in newly diagnosed GBM. Data collected within the Preston Robert Tisch Brain Tumor Center at Duke as part of the PRoGREss registry between 11/21/2011 and 10/10/2013 were queried retrospectively. In addition to demographic and clinical information, data were obtained from patient-reported outcome questionnaires including Functional Assessment of Cancer Therapy-Brain Cancer (FACT-Br) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Cox proportional hazard models were utilized to evaluate the effect of HRQoL and fatigue on overall survival. For this study, 322 subjects were identified. Mean age was 59 (SD = 13) years. KPS ranged from 40-100 with KPS ≥90 for 36.7%, KPS = 80 for 34.5%, KPS ≤ 70 for 21.4% and unknown for 7.5%. In univariate Cox analyses, the FACT-Br Total (HR = 0.986 (CI 95%: 0.98, 0.992) and FACIT-F (HR = 0.969 (CI 95%: 0.955, 0.982)) were both significant predictors of overall survival. Both the FACT-Br Total and FACIT-F added prognostic information beyond that provided by KPS alone (Likelihood ratio (LR) p = 0.003 and p = 0.004, respectively), but did not provide additional prognostic information when KPS, age, gender, and extent of resection were added to the multivariate model (LR p = 0.17 and p = 0.19, respectively). In fact, the strongest predictor of overall survival in this population was extent of resection (gross total resection vs biopsy, (HR = 3.11 (CI 95%: 2.12, 4.57))). Based on these findings, HRQoL and fatigue in newly diagnosed GBM are independent predictors of survival that provide incremental prognostic value to KPS but not to other prognostic factors such as extent of resection.

BACKGROUND: NELL2 expression has been shown to identify patients with posterior fossa ependymomas (PFEp) that exhibit prolonged survivals. We analyzed expression NELL2; KI-67; Tenascin C; CD34; VEGF; and CA IX as well as vascular density against post-operative survival (Progression Free and Overall Survival; PFS, OS) in 31 patients under the age of 22 years. METHODS: PFEp from patients aged 22 years or less were studied. H&E sections were reviewed for grade and vascular status and immunohistochemistry (IHC) was used to determine NELL2; KI-67; Tenascin C; CD34; VEGF; and CA IX status. RESULTS: 3 WHO Grade I, 19 Grade II and 9 Grade III PFEp were studied. Median follow-up time was 9.0 years; median survival was 6.1 years. NELL2 status correlated with PFS (Log Rank P-Value: 0.0220) and exhibited a strong trend towards prolonged OS (Log rank p = 0.0555). Peri-necrotic CAIX localization correlated with PFS (Log rank = 0.0041) and OS (Log rank p = 0.0010) All patients with a CA IX ≤ 5% total area localization were alive at last follow-up. Perinecrotic CAIX staining was also associated with CD34 density (p = .0057) though not with VEGF expression score. MIB-1 labeling index (LI) correlated with OS (p = 0.0185) and PFS (p = 0.0049). MIB-1 LI and perinecrotic CA IX individually correlated with PFS. The effect of perinecrotic CA IX remained when grade was added to a Cox model predicting PFS. There was a significant difference in the distributions of perinecrotic CA IX as stratified by NELL2 expression (Wilcoxon p = 0.0225) with NELL2 negative tumors exhibiting much stronger CA IX expression. CONCLUSIONS: Immunodetection of NELL2 expression was confirmed as a predictive biomarker for PFS in these tumors. This effect is related to the absence of necrosis, low vascular proliferation, low MIB-1 proliferation index, and the absence of CA IX expression. SECONDARY CATEGORY: Pediatrics.

BACKGROUND: With the exception of Burkitt lymphoma, almost all solid cancers are susceptible to infection with poliovirus, due to widespread ectopic expression of the poliovirus receptor, the onco-fetal cell adhesion molecule Necl5/CD155. We engineered a profoundly CNS-incompetent and genetically stable variant of polio through recombination of the cognate internal ribosomal entry site (IRES) with its counterpart from human rhinovirus type 2. The resulting PVSRIPO chimera is incapable of causing poliomyelitis or encephalitis in non-human primates or human subjects, even after high-dose intracerebral inoculation, but retains excellent cytotoxic properties in malignant cells. This is due to constitutively active signal transduction pathways via Raf-Erk MAPKs to the MAPK-interacting kinase, Mnk, and the translation apparatus. METHODS: Raf-Erk-Mnk signals favor translation of mRNAs with highly structured, encumbered 5' untranslated regions, typical for mRNAs encoding potent biological response modifiers, survival factors, growth factors or oncogenes. They afford an enormous advantage to PVSRIPO translation, causing irreversible lethal cytotoxicity as early as 60 min after infection. PVSRIPO infection of GBM produces drastic, violent cytotoxicity and a wide range of pro-inflammatory and immunogenic host responses. These are due to virally-induced ‘immunogenic cell death’, forceful activation of innate antiviral type 1 interferon responses, non-lethal infection and pro-inflammatory stimulation of tumor-associated macrophages/dendritic cells and stimulation of cytotoxic T-cell responses directed against the tumor. RESULTS: A currently accruing Phase-1 clinical trial of PVSRIPO with intratumoral, CED-mediated infusion in recurrent GBM is showing promise with the first patients experiencing durable complete clinical and near-complete radiographic responses >20 months post PVSRIPO infusion. The key to PVSRIPO oncolytic immunotherapy is the early acute phase of viral cytotoxicity after intratumoral infusion. Unhinged translation control, enabling unfettered viral, IRES-mediated initiation, is independent of the notorious intratumoral and inter-individual heterogeneity of advanced, treatment-refractory cancers. To define the molecular mechanism of PVSRIPO-mediated immunogenic cell death, we unraveled a signaling network centered on Raf-Erk-Mnk signals and their control over the Ser-Arg-rich protein kinase. CONCLUSIONS: Provided a solid mechanistic rationale exists for their use, oncolytic viruses such as PVSRIPO may induce tumor-cytotoxic, immune-modulatory and immune-stimulatory effects with an extent and biological range that are difficult to achieve with any other type of anti-cancer agent. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.