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Supplementary Table S3 from Bevacizumab Plus Irinotecan in Recurrent WHO Grade 3 Malignant Gliomas

Summary of adverse events with possible relation to study.

Ex vivo analysis of CMV pp65-specific CD8+ T cells in circulation before and after immunotherapy.

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

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: Although patients with newly diagnosed WHO grade 3 malignant glioma have a more favorable prognosis than those with WHO grade 4 malignant glioma, salvage therapies following recurrence offer essentially palliative benefit. We did a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan for patients with recurrent grade 3 malignant glioma.Experimental Design: Upon documentation of adequate safety among an initial cohort of nine patients treated with bevacizumab (10 mg/kg) and irinotecan every 14 days, a second cohort (n = 24) was treated with bevacizumab (15 mg/kg) every 3 weeks with irinotecan on days 1, 8, 22, and 29 of each 42-day cycle. For both cohorts, the dose of irinotecan was 340 mg/m2 for patients on enzyme-inducing antiepileptic drugs (EIAED) and 125 mg/m2 for patients not on EIAEDs. After each 6-week cycle, patients were evaluated with a physical examination and magnetic resonance imaging.Results: The 6-month progression-free survival was 55% (95% confidence interval, 36-70%). The 6-month overall survival was 79% (95% confidence interval, 61-89%). Twenty patients (61%) had at least a partial response. Outcome did not differ between the two treatment cohorts. Significant adverse events were infrequent and included a central nervous system hemorrhage in one patient, and one patient who developed thrombotic thrombocytopenic purpura.Conclusion: Bevacizumab and irinotecan is an active regimen with acceptable toxicity for patients with recurrent WHO grade 3 malignant glioma.

Median survival for glioblastoma (GBM) remains ex vivo analyses from this study found no change in the capacity of CMV pp65-specific T cells to gain multiple effector functions or polyfunctionality, which has been associated with superior antitumor efficacy. Previous studies have shown that dendritic cells (DC) could further enhance tumor-specific CD8+ T-cell polyfunctionality in vivo when administered as a vaccine. Therefore, we hypothesized that vaccination with CMV pp65 RNA-loaded DCs would enhance the frequency of polyfunctional CMV pp65-specific CD8+ T cells after ATCT. Here, we report prospective results of a pilot trial in which 22 patients with newly diagnosed GBM were initially enrolled, of which 17 patients were randomized to receive CMV pp65-specific T cells with CMV-DC vaccination (CMV-ATCT-DC) or saline (CMV-ATCT-saline). Patients who received CMV-ATCT-DC vaccination experienced a significant increase in the overall frequencies of IFNγ+, TNFα+, and CCL3+ polyfunctional, CMV-specific CD8+ T cells. These increases in polyfunctional CMV-specific CD8+ T cells correlated (R = 0.7371, P = 0.0369) with overall survival, although we cannot conclude this was causally related. Our data implicate polyfunctional T-cell responses as a potential biomarker for effective antitumor immunotherapy and support a formal assessment of this combination approach in a larger randomized study.Significance: A randomized pilot trial in patients with GBM implicates polyfunctional T-cell responses as a biomarker for effective antitumor immunotherapy. Cancer Res; 78(1); 256–64. ©2017 AACR.

BACKGROUND: The NIH Revitalization Act, implemented 29 years ago, set to improve the representation of women and minorities in clinical trials. In this study, we investigate progress made in all phase therapeutic clinical trials for neuroepithelial CNS tumors stratified by demographic-specific age-adjusted disease incidence and mortality. Additionally, we identify workforce characteristics associated with clinical trials meeting established accrual benchmarks. METHODS: Registry study of published clinical trials for World Health Organization defined neuroepithelial CNS tumors between January 2000 and December 2019. Study participants were obtained from PubMed and ClinicalTrials.gov. Population-based data originated from the CBTRUS for incidence analyses. SEER-18 Incidence-Based Mortality data was used for mortality analysis. Descriptive statistics, Fisher exact, and χ (2) tests were used for data analysis. RESULTS: Among 662 published clinical trials representing 49 907 participants, 62.5% of participants were men and 37.5% women (P < .0001) representing a mortality specific over-accrual for men (P = .001). Whites, Asians, Blacks, and Hispanics represented 91.7%, 1.5%, 2.6%, and 1.7% of trial participants. Compared with mortality, Blacks (47% of expected mortality, P = .008), Hispanics (17% of expected mortality, P < .001) and Asians (33% of expected mortality, P < .001) were underrepresented compared with Whites (114% of expected mortality, P < .001). Clinical trials meeting accrual benchmarks for race included minority authorship. CONCLUSIONS: Following the Revitalization Act, minorities and women remain underrepresented in therapeutic clinical trials for neuroepithelial tumors, relative to disease incidence and mortality. Study accrual has improved with time. This study provides a framework for clinical trial accrual efforts and offers guidance regarding workforce considerations associated with enrollment of underserved patients.

D2C7-immunotoxin (IT), a dual-specific IT targeting wild-type epidermal growth factor receptor (EGFR) and mutant EGFR variant III (EGFRvIII) proteins, demonstrates encouraging survival outcomes in a subset of patients with glioblastoma. We hypothesized that immunosuppression in glioblastoma limits D2C7-IT efficacy. To improve the response rate and reverse immunosuppression, we combined D2C7-IT tumor cell killing with αCD40 costimulation of antigen-presenting cells. In murine glioma models, a single intratumoral injection of D2C7-IT+αCD40 treatment activated a proinflammatory phenotype in microglia and macrophages, promoted long-term tumor-specific CD8 + T cell immunity, and generated cures. D2C7-IT+αCD40 treatment increased intratumoral Slamf6 + CD8 + T cells with a progenitor phenotype and decreased terminally exhausted CD8 + T cells. D2C7-IT+αCD40 treatment stimulated intratumoral CD8 + T cell proliferation and generated cures in glioma-bearing mice despite FTY720-induced peripheral T cell sequestration. Tumor transcriptome profiling established CD40 up-regulation, pattern recognition receptor, cell senescence, and immune response pathway activation as the drivers of D2C7-IT+αCD40 antitumor responses. To determine potential translation, immunohistochemistry staining confirmed CD40 expression in human GBM tissue sections. These promising preclinical data allowed us to initiate a phase 1 study with D2C7-IT+αhCD40 in patients with malignant glioma (NCT04547777) to further evaluate this treatment in humans.

Background Spirituality can impact patients’ attitudes and decisions about treatment and end-of-life care when coping with cancer. Previous studies documented health-related quality of life (HRQoL) and spiritual well-being (SWB) as positively correlated within a general cancer patient population, but little is known about their association in the primary brain tumor population. We sought to measure SWB in primary brain tumor patients and evaluate whether it was associated with HRQoL. Methods Six-hundred and six patients treated at The Preston Robert Tisch Brain Tumor Center at Duke between December 16, 2013 and February 28, 2014 with data in the PRoGREss registry are included in this retrospective analysis. Each patient completed the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being 12 (FACIT-Sp-12) and -Fatigue (FACIT-F), and the Functional Assessment of Cancer Therapy-General and -Brain (FACT-G and FACT-Br). Results Mean age was 49.1 years (SD = 13.5 years), male (N = 328, 54.1%), married (N = 404, 66.7%), at least college-educated (N = 381, 62.9%), and diagnosed with a high-grade glioma (N = 412, 68.0%). Multiple regression analyses were performed on both the FACT-G and the FACT-Br using the FACIT-Sp-12 sub-scales of Meaning/Peace and Faith, FACIT-F, belief in God or a higher power, prayer, gender, tumor grade, and Karnofsky Performance Status (KPS) as predictors. We found that greater SWB (measured by FACIT-Sp-12) was associated with better HRQoL (measured by FACT-G and FACT-Br; p < .0001). Conclusion The association between reported SWB and reported improved HRQoL emphasizes the importance of spirituality in primary brain tumor patients, suggesting SWB must be considered in strategies to improve HRQoL.

BACKGROUND Outcomes of recurrent pediatric high grade glioma (pHHG) are poor with a median overall survival (OS) of < 6 months. Viral immunotherapy such as the polio:rhinovirus chimera, PVSRIPO, is a novel treatment approach for recurrent pHHG. PVSRIPO is genetically engineered to prevent neurovirulence. In adults with recurrent glioblastoma treated with PVSRIPO, 21% survived > 36 months. The poliovirus receptor, CD155, is ubiquitously expressed in malignant pediatric brain tumors including pHHG. METHODS The primary objective of this Phase 1b clinical trial was to evaluate the safety and feasibility of PVSRIPO for recurrent pHGG. PVSRIPO was given at a single dose, 5x107 50% tissue-culture infectious dose (TCID50) administered by convection enhanced delivery (CED) to children with biopsy-confirmed recurrent pHHG between ≥ 1 and ≤ 5.5 in diameter. 3 mL of PVSRIPO was delivered at 0.5 mL/hr via a single catheter. RESULTS Eight patients were treated with PVSRIPO including 5 males and 3 females with a median age of 16.5 (range 9-19). Six patients had recurrent glioblastoma, 2 had recurrent anaplastic astrocytoma. The median number of previous recurrences prior to enrollment was 3.5 (range 1-5). Four patients received bevacizumab on-study for treatment-related peritumoral inflammation/edema. Six of 8 patients experienced 26 treatment related adverse events (AEs) possibly, probably, or definitely related to protocol treatment. There were no Grade 4 or 5 AEs. There were 3 Grade 3 AEs: 2 headaches and 1 seizure. There were no AEs related to biopsy or CED catheter insertion/removal. Median OS was 4.13 months (range 1.23-NA). One patient is currently alive at > 21 months. Monocyte and T cell inflammatory phenotypes and total CD4+ T cells were increased in peripheral blood after treatment. CONCLUSIONS CED of PVSPRIO is both safe and feasible for the treatment of recurrent pHHG. Histologic correlative results will also be presented.

Glioblastoma is the most common primary malignant brain tumor in adults and outcomes remain poor despite the current standard of care multimodal therapy. Oncolytic virotherapy utilizes engineered viruses to exert an anti-tumor effect via both direct oncolysis and stimulation of an immune response within the tumor microenvironment, turning tumors from "cold" to "hot." This has shown promise as a novel therapeutic modality and attempts to circumvent the challenges associated with traditional treatments. Many oncolytic viruses have been investigated in completed and ongoing clinical trials and while safety has been demonstrated, clinical outcomes have been variable, often with only a subgroup of patients showing a significant response. This review summarizes these studies, addresses relevant technical aspects of oncolytic virus administration, and highlights practical considerations to assist providers in appropriately caring for patients treated with oncolytic virotherapy. Additionally, future directions within the field that may help to maximize efficacy of this modality are discussed.

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

Primary central nervous system lymphoma (PCNSL) is a subtype of non-Hodgkin’s lymphoma that involves the brain, spinal cord, or leptomeninges, without evidence of systemic disease. This rare disease accounts for ~ 3% of all primary central nervous system (CNS) tumors. Methotrexate-based regimens are the standard of care for this disease with overall survival rates ranging from 14 to 55 months. Relapse after apparent complete remission can occur. We sought to understand the outcomes of patients who relapsed. This is an IRB-approved investigation of patients treated at our institution between 12/31/2004 and 10/12/2016. We retrospectively identified all cases of PCNSL as part of a database registry and evaluated these cases for demographic information, absence or presence of relapse, location of relapse, treatment regimens, and median relapse-free survival. This analysis identified 44 patients with a pathologically confirmed diagnosis of PCNSL. Mean age at diagnosis was 63.1 years (range 20–86, SD = 13.2 years). Of the 44 patients, 28 patients successfully completed an initial treatment regimen without recurrence or toxicity that required a change in therapy. Relapse occurred in 11 patients with the location of relapse being in the CNS only (n = 5), vitreous fluid only (n = 1), outside CNS only (n = 3), or a combination of CNS and outside of the CNS (n = 2). Sites of relapse outside of the CNS included testes (n = 1), lung (n = 1), adrenal gland (n = 1), kidney/adrenal gland (n = 1), and retroperitoneum (n = 1). Median relapse-free survival after successful completion of therapy was 6.7 years (95% CI 1.1, 12.6). After successful initial treatment, PCNSL has a propensity to relapse, and this relapse can occur both inside and outside of the CNS. Vigilant monitoring of off-treatment patients with a history of PCNSL is necessary to guide early diagnosis of relapse and to initiate aggressive treatment.

Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is an incurable disease that has an inevitable tendency to recur following standard of care surgery, radiotherapy, and temozolomide chemotherapy. There is an urgent need for improved medical therapies. The topoisomerase I inhibitor irinotecan has been investigated and used in the treatment of GBM for over 20 years. Clinical trials investigating irinotecan as monotherapy and in combination with temozolomide and bevacizumab have failed to show an overall survival benefit for newly diagnosed and recurrent GBM. Consequently, irinotecan is not commonly recommended for GBM treatment. However, these trials were conducted prior to the advent of molecularly-guided GBM subtyping, which is now a cornerstone of glioma diagnostics according to the updated WHO 2021 classification. To understand the extent to which molecularly-defined glioma subgroups differentially respond to clinically relevant therapies, we investigated the sensitivity of GBM patient-derived xenografts (PDXs) against a panel of chemotherapeutic agents, including temozolomide, bevacizumab, and irinotecan. All GBM PDXs (n=9) were responsive to irinotecan when grown as subcutaneous tumors. Two PDX lines exhibited hypersensitivity to irinotecan, which was marked by treatment-induced regression of subcutaneous tumors and increased median survival of 61 and 90+ days. Molecular analyses revealed that these hypersensitive lines were both ATRX-deficient tumors that displayed the alternative lengthening of telomeres (ALT) phenotype, while the less sensitive lines were all ATRX-intact and demonstrated TERT activation. One of the hypersensitive lines was IDH1R132H/WT while the other was IDH1R132H/− (historically termed secondary GBM; grade 4 astrocytoma per 2021 WHO classification). Cell-based studies showed that irinotecan sensitivity did not correlate with D-2HG producing capacity of the cells and was not impacted by inhibition of the mutant IDH1 enzyme. Irinotecan treatment significantly prolonged survival of orthotopic ALT+ PDXs relative to a vehicle control (64 days versus 41.5 days median survival). These results suggest that ALT+ gliomas may be particularly sensitive to topoisomerase inhibitor therapy. Our study highlights the need to interpret glioma clinical trial results in light of key molecular biomarkers, including indicators of ALT activity (e.g. ATRX deficiency, ultrabright telomeric foci, and C-circles). In addition, our results suggest that ALT-related biomarkers may be useful for identifying glioma patients who may benefit from topoisomerase inhibitor therapy. Citation Format: Stephen T. Keir, Heng Liu, Justin T. Low, Christopher J. Pirozzi, Nathan Reynolds, Eric S. Lipp, Annick Desjardins, Henry S. Friedman, Mustafa Khasraw, Darell D. Bigner, David M. Ashley, Matthew S. Waitkus. Alternative lengthening of telomeres is associated with hypersensitivity to topoisomerase 1 inhibition in glioblastoma xenograft models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4924.

Glioblastoma (GBM) is the most common adult primary malignant brain tumor and is associated with a dire prognosis. Despite multi-modality therapies of surgery, radiation, and chemotherapy, its 5-year survival rate is 6.8%. The presence of the blood-brain barrier (BBB) is one factor that has made GBM difficult to treat. Convection-enhanced delivery (CED) is a modality that bypasses the BBB, which allows the intracranial delivery of therapies that would not otherwise cross the BBB and avoids systemic toxicities. This review will summarize prior and ongoing studies and highlights practical considerations related to clinical care to aid providers caring for a high-grade glioma patient being treated with CED. Although not the main scope of this paper, this review also touches upon relevant technical considerations of using CED, an area still under much development.

Introduction: Estimating the risk of extended length of stay (LOS) or non-routine discharge disposition is helpful in surgical decision-making for patients with brain metastases (BM). In 2020, an online calculator was introduced by Khalafallah et al. that stratified the risk of patients with brain tumors based on poor surgical outcomes. We applied the calculator to our population of BM patients to determine its generalizability and validity. Methods: We included BM patients who underwent a cranial procedure between 2015 and 2018 at a single academic institution. Patient age, race, marital status, admission status, KPS score, and medical co-morbidities (5-point modified frailty index (mFI-5)) were included in the analysis. We calculated the areas under the Receiver Operating Characteristics (ROC) curves to determine the validity of the model proposed in predicting extended LOS (>7 days) and need for specialty care at discharge (non-routine discharge disposition). Results: We analyzed 244 patients (mean age 61.2 years (SD 11.1), 57.0% female, and 78.1% Caucasian). The areas under the ROC curves were 0.8427 and 0.8422 for extended LOS and non-routine discharge disposition, suggesting high accuracy of the models for these outcomes. However, the (mFI-5) was not a significant predictor of either outcome in our multivariate analyses. Conclusions: We validated Khalafallah et al.’s predictive models of extended LOS and non-routine discharge disposition in our patient population, which included a broader range of surgical procedures. Further investigation of this model could clarify how the type of neurosurgical procedure influences outcomes, the role of the mFI-5, and its overall generalizability.

INTRODUCTION Glioblastoma (GBM) is the most aggressive primary brain tumour in adults, leading to universal recurrence despite aggressive surgical and chemotherapeutic treatment. Post-recurrence, median overall survival is 6 to 10 months and treatment options are very limited. One of the biggest challenges in treating GBM is achieving high local drug concentration; systemic administration of cytotoxic agents has failed in the past due to this limitation. Convection enhanced delivery (CED) is a ‘direct-to-brain’ drug delivery method that previously demonstrated its usefulness in overcoming this challenge. MTX110 (Midatech Pharma Ltd) is a water-soluble form of panobinostat, that demonstrated cytotoxic activity in 4 GBM cell lines (U87MG, U251MG, U118MG and T98G) with an average IC50 value around 40nM which also translated into pre clinical in vivo efficacy, in combination with radiotherapy1. Delivery of MTX110 via an implanted pump and CED catheter system in patients with GBM appears to be an attractive treatment option, that allows for therapeutic doses of the drug to be delivered weekly directly to the tumour, thus avoiding systemic administration and therefore toxicity. This has previously been demonstrated in investigator-initiated studies of paediatric patients with diffuse intrinsic pontine glioma. METHOD MAGIC-G1 study is a Phase 1 two-cohort dose-escalating study that will assess safety and feasibility of intermittent intratumoral administration of MTX110 by CED to rGBM patients; either as a single agent (Cohort 1) or in combination with lomustine (Cohort 2). Eligible patients will have a catheter system and an abdominal refillable pump implanted in an aseptic manner, with the tip of the catheter positioned stereotactically at the centre of the tumour. 48-hour infusions will be administered weekly until disease progression and doses of 30, 60 and 90 mM will be investigated. Cohort 1 recruitment will be completed before Cohort 2 starts dosing. Study results are expected in 2023.

BACKGROUND D2C7-IT, a novel immunotoxin-based cytotoxic therapy, targets epidermal growth factor receptor (EGFR) and mutant EGFR variant III. In preclinical studies, D2C7-IT kills tumor cells and prolongs survival, but is unable to generate cures in all animals. We hypothesized that immunosuppression in glioblastoma limits D2C7-IT efficacy. Eliminating glioblastoma immunosuppression via CD40 co-stimulation is anticipated to enhance D2C7-IT-induced antitumor responses. In murine glioma models, CED of D2C7-IT+αCD40 generated cures and long-term tumor-specific adaptive immunity. Hence, we are conducting a phase 1 trial of D2C7-IT+2141-V11 (αhuman-CD40) administered via CED in rMG patients. METHODS Eligibility includes adult patients with solitary supratentorial rMG (WHO grade 3/4); ≥ 4 weeks after chemotherapy, bevacizumab, or study drug; adequate organ function; and KPS ≥ 70%. Cohorts of 3 patients are treated with increasing doses of 2141-V11 to determine the maximum tolerated dose when administered sequentially following D2C7-IT (166,075 ng) via CED at 0.5 mL/hr. Five dose levels (DLs) are evaluated (2141-V11 at: #1: 0.70 mg; #2: 2.0 mg; #2**: 3.0 mg #2*: 4.0 mg; #3: 7.0 mg). RESULTS As of May 29, 2022, 13 patients were treated (3 patients on DL1, DL2, and DL2**; 2 patients on DL3 and DL2*). No dose-limiting toxicities were observed; however, lower DLs were added due to higher frequency of adverse events (AEs) expected with D2C7-IT+2141-V11 with DL3 and DL2* (fever, neurologic symptoms). All patients remain alive 0.7-10.6 months after therapy. Grade ≥ 2 AEs due to D2C7-IT+2141-V11 include: headache (grade 3, n = 1; grade 2, n = 4); pyramidal tract disorder (grade 3, n = 1; grade 2, n = 2); paresthesia (grade 3, n = 1); dysphasia (grade 3, n = 1); seizures (grade 2; n = 2); fever (grade 2; n = 2); and one each of grade 2 depressed level of consciousness, fatigue, and concentration impairment. Enrollment is ongoing. CONCLUSIONS Intratumoral administration of D2C7-IT+2141-V11 via CED is safe, encouraging efficacy results are observed.

BACKGROUND Nausea and vomiting remain the most feared cancer treatment-related side effects. Trials establishing antiemetic guidelines exclude malignant glioma (MG) patients. In MG patients receiving radiation with concurrent temozolomide, chemoradiation-induced nausea and vomiting (cRINV) rates are 35 and 26%, respectively, which reduce quality of life, treatment adherence, and potentially cancer control.OBJECTIVES: In a randomized phase II open label trial, we compared patient satisfaction and efficacy of ondansetron monotherapy (short-acting 5HT3-RA; 3h half-life) vs. rolapitant (long-acting NK1-RA; 180h half-life) plus ondansetron in preventing cRINV during 6-weeks of daily temozolomide (75 mg/m2/dX42d) with radiation. METHODS Fifty-three eligible patients receiving chemoradiation were randomized to Arm-A (ondansetron 8mg Days 1-42, rolapitant 180mg on Day 21) or Arm-B (rolapitant on Day 1 plus daily ondansetron). Primary endpoint included the percentage achieving cRINV-complete response (CR; no vomiting or antiemetic rescue) during the first 2-weeks of radiation. Secondary endpoints included cRIN/cRIV rates, preference for rolapitant plus ondansetron, and toxicity. RESULTS Forty-eight initiated protocol treatment. Mean age=53, 58% male, median KPS 90%, 71% low alcohol N/V risk factor, 73% glioblastoma. During the first 2-weeks of radiation, cRINV-CR was 60% for 25 evaluable patients receiving ondansetron monotherapy and 65% for 23 receiving rolapitant/ondansetron (p< 0.71). Patient-reported cRINV-CR was 61% and 74%, respectively (p< 0.41); cRIN rates (44% Arm-A; 53% Arm-B) were more than cRIV rates (28% Arm-A; 11% Arm-B). More patients receiving ondansetron alone vomited the first 2-weeks (22%) than with rolapitant/ondansetron (0%); p< 0.05. Among 32 patients who completed the study, patients preferred ondansetron (63%) over rolapitant/ondansetron (19%); p< 0.0039; 19% had no preference. Adverse events attributable to antiemetic treatment (fatigue/constipation) were all grade 1-2. CONCLUSIONS While patients prefer ondansetron monotherapy, there was no difference in cRINV-CR between the first 2-week treatments and some had less vomiting with rolapitant plus ondansetron. We will present overall N/V results.

CINV remains a distressing side effect experienced by glioma patients receiving multi-day temozolomide therapy, in spite of guideline-based antiemetic therapy with selective serotonin-receptor-antagonists. Antiemetic research with aprepitant has routinely excluded glioma patients. In this randomized open-label phase II study, use of a nonstandard 5-day regimen of aprepitant for glioma patients was investigated. One hundred thirty-six glioma patients receiving their first cycle of adjuvant temozolomide (150–200 mg/m2/day × 5 days every 28 days) were randomized to Arm-A (ondansetron 8 mg days 1–5 with aprepitant day 1: 125 mg, days 2–5: 80 mg) or Arm-B (ondansetron). Randomization was stratified by tumor grade and number of prior chemotherapy regimens. The primary endpoint was the percentage of patients achieving complete control (CC), defined as no emetic episode or antiemetic rescue medication over the 7-day study period. Secondary endpoints included CINV efficacy in the acute phase (≤ 24 h) and delayed phase (days 2–7), as well as safety and quality of life (QoL). Patients were 61% male, 97% white, 48% with KPS > 90%, 60% non-smokers, mean age 54, 92% with low alcohol use, and 46% with a CINV history. The CC was 58.6% (Arm-A) and 54.5% (Arm-B). Acute-complete response (CR) rates, defined as CC on day 1 in Arm-A and -B, were 97.1% and 87.9%, respectively (p = 0.056). Treatment-related toxicities were mild or moderate in severity. Aprepitant plus ondansetron may increase acute-CR, may have benefit regarding CINV’s effect on QoL, and is safe for 5-day temozolomide compared to ondansetron. This study provides no evidence that aprepitant increases CC rate over ondansetron alone.

Background and purpose Little is known about complementary and integrative health intervention usage in the primary brain tumor population. We aimed to identify the percentage of patients using these practices and explore the impact on quality of life. Materials and methods Clinical records from patients seen in clinic between December 16, 2013 and February 28, 2014 were reviewed retrospectively. The questionnaires used were a modified version of the International Complementary and Alternative Medicine Questionnaire, the Functional Assessment of Cancer Therapy- Brain Cancer and the Functional Assessment of Chronic Illness Therapy- Fatigue. Results 76% of patients utilized a complementary and integrative health modality. The most frequently reported modalities used were vitamins, massage, and spiritual healing, prayer, diet and meditation. Conclusion These results confirm the usage of complementary and integrative health practices within the primary brain tumor population; however, there was no evidence of association between use and quality of life.

INTRODUCTION Neurocognitive dysfunction can result from radiation therapy which is the mainstay of treatment for high-grade glioma, particularly glioblastoma. Preclinical observations found that BMX-001, a novel metalloporphyrin, acts as a radioprotectant for normal CNS cells yet as a radiosensitizer to cancer cells in human GBM xenograft experiments. In a phase 1 study evaluating the safety of BMX-001 in combination with concurrent radiation therapy and temozolomide, we further studied neurocognitive function before and after concurrent radiation therapy and temozolomide in newly diagnosed high-grade glioma patients. METHODS We performed a phase 1 study of BMX-001 combined with radiation therapy (6-week total of 59.4-60 Gy) and temozolomide (75 mg/m2/day for 42 days). We administered BMX-001 as a subcutaneous injection at a loading dose before radiation therapy and temozolomide and then subsequent doses twice weekly for eight weeks. A key secondary endpoint was the evaluation of neurocognition. We performed neurocognitive testing with the computerized program CNS Vital Signsâ. This battery consists of seven tests: verbal memory, visual memory, finger tapping, symbol digit coding, the Stroop Test, a test of shifting attention, and a continuous performance test. We defined neurocognitive impairment at baseline as a z-score ≥ 1.5 SDs below the normative mean. We described improvements or declines in neurocognition at 2 and 6 months from baseline. RESULTS Fifteen patients (age 19-80 years) enrolled and underwent neurocognitive testing before and after RT. All patients had WHO grade 4 glioblastoma. Most subjects had neurocognitive impairment ranging from 46.7-to 80% on specific neurocognitive tests. At two months (N=15) and six months (N=9), most testing demonstrated improved neurocognitive performance. CONCLUSIONS Neurocognitive function is maintained and can improve after concurrent radiation therapy and temozolomide in this high-grade glioma cohort treated with BMX-001 during concurrent radiation therapy and temozolomide.

Purpose: At diagnosis and throughout the disease course, patients with high-grade glioma (HGG) experience a diminished quality of life (QOL) and increased fatigue. Naltrexone, an orally semisynthetic opiate antagonist, is FDA-approved for the treatment of heroin/alcohol addiction, and low dose naltrexone (LDN) has been observed to improve QOL and lower fatigue in other neurological illnesses, such as multiple sclerosis. LDN is believed to function as a partial agonist and can lead to shifts in neurochemicals that reduce fatigue. Based on this, we sought to study whether LDN has an impact on QOL and fatigue in patients with HGG. Methods: In a placebo-controlled, double-blind study, we randomized 110 HGG patients to receive placebo (N=56) or LDN 4.5 mg orally at night (N=54). Subjects received LDN or placebo at day 1 of concurrent radiation and temozolomide therapy and continued for 16 weeks. Change from baseline in patient-reported outcomes of QOL (Functional Assessment of Cancer Therapy-Brain) and fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) was assessed. Results: Demographics were WHO grade IV (85%), male (56%), KPS 90-100 (51%), grossly resected (55%), and mean age of 56 years. QOL and fatigue changes between baseline and post concurrent chemotherapy and radiation therapy were not significantly different between patients receiving LDN or placebo. The adverse event profile for LDN and placebo were similar and attributed to concomitant use of temozolomide. Conclusions: While safe to administer, LDN has no effect on QOL and fatigue in HGG patients during concurrent chemotherapy and radiation therapy. United States National Library of Medicine Clinical Trials.gov NCT01303835, Date 2/25/2011

ObjectivesStandard 6-week and hypofractionated 3-week courses of adjuvant radiation therapy (RT) are both options for older patients with glioblastoma (GBM), but deciding the optimal regimen can be challenging. This analysis explores clinical factors associated with selection of RT course, completion of RT, and outcomes following RT.Materials and MethodsThis IRB-approved retrospective analysis identified patients ≥70 years old with GBM who initiated adjuvant RT at our institution between 2004 and 2016. We identified factors associated with standard or hypofractionated RT using the Cochran-Armitage trend test, estimated time-to-event endpoints using the Kaplan-Meier method, and found predictors of overall survival (OS) using Cox proportional hazards models.ResultsSixty-two patients with a median age of 74 (range 70–90) initiated adjuvant RT, with 43 (69%) receiving standard RT and 19 (31%) receiving hypofractionated RT. Selection of short-course RT was associated with older age (p = 0.04) and poor KPS (p = 0.03). Eight (13%) patients did not complete RT, primarily for hospice care due to worsening symptoms. After a median follow-up of 37 months, median OS was 12.3 months (95% CI 9.0–15.1). Increased age (p < 0.05), poor KPS (p < 0.0001), lack of MGMT methylation (p < 0.05), and lack of RT completion (p < 0.0001) were associated with worse OS on multivariate analysis. In this small cohort, GTV size and receipt of standard or hypofractionated RT were not associated with OS.ConclusionsIn this cohort of older patients with GBM, age and KPS was associated with selection of short-course or standard RT. These regimens had similar OS, though a subset of patients experienced worsening symptoms during RT and discontinued treatment. Further investigation into predictors of RT completion and survival may help guide adjuvant therapies and supportive care for older patients.

e14015 Background: D2C7 immunotoxin (D2C7-IT) is a dual-specific recombinant immunotoxin comprising an EGFR wild-type and mutant-specific (EGFRvIII) monoclonal antibody (Ab) fragment and a genetically engineered form of the Pseudomonas exotoxin. When injected directly into the tumor by convection enhanced delivery (CED), immunotoxins induce both direct tumor killing and secondary immune responses by activation of CD4+ and CD8+ T-cells. Tumor-associated macrophages (TAMs) are the most prominent glioma-infiltrating immune cells and constitute up to 40% of the tumor mass. Upon binding of D2C7-IT to EGFR and cellular internalization, the Pseudomonas exotoxin moiety of the D2C7-IT kills residual GBM cells, upregulates proinflammatory CD40, and induces pattern recognition receptor pathway transcriptome expression. This potentially creates a proinflammatory glioma microenvironment where TAM activation may be further stimulated by sequential CED of 2141-V11, an Fc engineered anti-human CD40 agonist antibody developed at Rockefeller University. We are conducting a first in human trial of the combination of D2C7-IT + 2141-V11 administered via CED in recurrent MG patients. Methods: Eligibility includes adult patients with recurrence of a solitary supratentorial WHO grade 3 or 4 MG; ≥ 4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS ≥ 70%. Cohorts of 3 patients are treated with increasing levels of 2141-V11 to determine the maximum tolerated dose (MTD) of the compound administered intratumorally in conjunction with D2C7-IT. Dose escalation and de-escalation are managed using a modified Bayesian optimal interval (BOIN) design to identify the MTD. Intratumoral administration of D2C7-IT via CED (4612 ng/mL over 72 hours) is followed by a 7-hour infusion of 2141-V11, both infused at 0.5 mL/hr. 2141-V11 is dose-escalated to determine the MTD when combined with D2C7-IT. Four dose levels (DL) are planned: #1: 0.70 mg; #2: 2.0 mg; #3: 7.0 mg; #4: 21.0 mg. Results: As of February 7, 2022, three patients were treated at DL1 and DL2, and two patients at DL3. No DLTs have been observed, and all eight patients remain alive and in observation on study after 7.0, 6.5, 6.0, 4.4, 2.8, 2.4, 0.9 and 0.5 months. Early signs of tumor response have been observed, with one patient at DL1 and 2 patients at DL2 without radiographic evidence of active tumor. Grade 2 or higher AEs due to D2C7-IT and/or 2141-V11 include: headache (grade 3, n = 1; grade 2, n = 2); paresthesia (grade 3, n = 1; grade 2, n = 1); dysphasia (grade 3, n = 1); pyramidal tract disorder (grade 3, n = 1; grade 2, n = 1); and depressed level of consciousness (grade 2, n = 1). Enrollment is ongoing. Conclusions: Intratumoral administration of D2C7-IT + 2141-V11 via CED is safe, and encouraging efficacy results have been observed. Clinical trial information: NCT04547777.

TPS2076 Background: High-grade gliomas (HGGs) are immunologically ‘cold’ tumors. This phenomenon is partly due to reduced expression of major histocompatibility class (MHC) I on the surface of tumor cells, which prevents CD8+ cytotoxic T lymphocyte activity (CTLs). Blockade of proprotein convertase subtilisin/kexin type 9 (PCSK9) increases MHC class I expression, enhances CTL tumoral infiltration, and potentiates checkpoint inhibition in vivo. Evolocumab is an FDA-approved fully human IgG2 monoclonal antibody PCSK9 inhibitor which is clinically indicated for hyperlipidemia. This study seeks to determine whether evolocumab can cross the blood-brain barrier (BBB) and enhance MHC I expression on resected tumor cells, serving as a potential future adjunct for immunotherapy. Methods: This study will enroll ten patients over 18 years who have newly diagnosed or recurrent HGG. These patients will also need to be undergoing resection of their tumor as part of their planned treatment pathway. Following informed consent, patients will receive evolocumab (420mg, subcutaneously) 7-14 days before surgical debulking of the tumor. We will collect tissue which is not required for histological tumor analysis and compare it with a contemporaneous matched control cohort. This will consist of resected tumor specimens from patients not treated with evolocumab. Quantification of the drug will be performed using mass spectroscopy, flow cytometry, and single-cell sequencing. The primary objective of this study is to evaluate whether evolocumab can cross the BBB and be measured in resected tumor specimens taken from patients with HGG. Secondary objectives include an analysis of lipid metabolism and MHC-I expression on the tumor via flow cytometry and CITEseq. Wilcoxon rank-sum test or a two-sample t-test, will compare groups for these endpoints. Exploratory analyses will determine if evolocumab leads to changes in tumorigenic pathways and the immune profile of tumor infiltrating lymphocytes (TILs). Bioinformatic analyses will be performed using protein set enrichment, gene ontology (GO) annotations, and search tools from the retrieval of interactive genes/proteins (STRING). Progress: The study was activated on 10/04/2021 (NCT04937413) and at the time of submission has enrolled 5 participants (4 to control arm, 1 to intervention arm). Clinical trial information: NCT04937413.

INTRODUCTION While primary GBM is largely heterogeneous and devoid of homogeneously expressed neoantigens, mutant IDH1 (R132H) is a uniformly expressed hallmark in >70% of low grade gliomas. As such, IDH1 mutations represent a potentially valuable vaccination target. METHODS Here, we report an update on the immunogenicity results of the mutant IDH1 peptide vaccine alone and in combination with temozolomide (TMZ). In the phase I RESIST clinical trial (NCT02193347), patients with recurrent and resectable IDH1 R132H mutant grade 2 glioma received peptide vaccinations composed of 500 µg of mutant IDH1 peptide and 150 µg of GM-CSF mixed 1:1 with Montanide adjuvant prior to surgical resection. Vaccines 1, 2, and 3 were given 15 (+/-) 3 days apart. 7-12 days after vaccine 3, patients underwent standard of care tumor (SOC) resection. After resection, patients with grade 2 gliomas were given up to 15 doses of peptide vaccine in combination with TMZ regimens while patients with transformed grade 3 gliomas were given up to 15 doses of peptide vaccine in combination with SOC radiation therapy + TMZ regimens. T cell responses against the mutant peptide were measured after vaccine 3 using IFN-γ ELISPOT and intracellular flow cytometry for IL-2, TNFα,and IFNγ. RESULTS 3/20 patients were taken off the study before completion of study related activities. 1/20 patients progressed before completion of all vaccines. Out of 134 total doses of vaccine delivered, only one dose generated a grade 2 or higher injection site reaction according to the CTCAE guidelines. Vaccination with the mutant peptide led to an overall increase in IFN-γ+ spot-forming splenocytes specific to the mutant peptide (p=0.0408). CONCLUSION Administering the mutant IDH1 peptide vaccine in patients with recurrent IDH-mutant gliomas was able to induce anti-IDH1 R132H immune responses in this initial phase I study.

At diagnosis and throughout the disease course, patients with high-grade glioma (HGG) experience a diminished quality of life (QOL) and increased fatigue. Naltrexone, an orally semisynthetic opiate antagonist, is FDA-approved for the treatment of heroin/alcohol addiction, and low-dose naltrexone (LDN) has been observed to improve QOL and lower fatigue in other neurological illnesses, such as multiple sclerosis. LDN is believed to function as a partial agonist and can lead to shifts in neurochemicals that reduce fatigue. Based on this, we sought to study whether LDN has an impact on QOL and fatigue in patients with HGG.In a placebo-controlled, double-blind study, we randomized 110 HGG patients to receive placebo (N = 56) or LDN 4.5 mg orally at night (N = 54). Subjects received LDN or placebo at day 1 of concurrent radiation and temozolomide therapy and continued for 16 weeks. Change from baseline in patient-reported outcomes of QOL (Functional Assessment of Cancer Therapy-Brain) and fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) was assessed.Demographics were WHO grade IV (85%), male (56%), KPS 90-100 (51%), grossly resected (55%), and mean age of 56 years. QOL and fatigue changes between baseline and post concurrent chemotherapy and radiation therapy were not significantly different between patients receiving LDN or placebo. The adverse event profiles for LDN and placebo were similar and attributed to concomitant use of temozolomide.LDN has no effect on QOL and fatigue in HGG patients during concurrent chemotherapy and radiation therapy.United States National Library of Medicine Clinical Trials.gov NCT01303835, Date 2/25/2011.

SummaryPurpose Galunisertib, a TGF-β inhibitor, has demonstrated antitumor effects in preclinical and radiographic responses in some patients with malignant glioma. This Phase 1b/2a trial investigated the clinical benefit of combining galunisertib with temozolomide-based radiochemotherapy (TMZ/RTX) in patients with newly diagnosed malignant glioma (NCT01220271). Methods This is an open-label, 2-arm Phase 1b/2a study (N = 56) of galunisertib (intermittent dosing: 14 days on/14 days off per cycle of 28 days) in combination with TMZ/RTX (n = 40), versus a control arm (TMZ/RTX, n = 16). The primary objective of Phase 1b was to determine the safe and tolerable Phase 2 dose of galunisertib. The primary objective of Phase 2a was to confirm the tolerability and pharmacodynamic profile of galunisertib with TMZ/RTX, and the secondary objectives included determining the efficacy and pharmacokinetic (PK) profile of galunisertib with TMZ/RTX in patients with glioblastoma. This study also characterized the changes in the major T-cell subsets during TMZ/RTX plus galunisertib treatment. Results In the Phase 2a study, efficacy results for patients treated with galunisertib plus TMZ/RTX or TMZ/RTX were: median overall survival (18.2 vs 17.9 months), median progression-free survival (7.6 vs 11.5 months), and disease control rate (80% [32/40] vs 56% [9/16] patients) respectively. PK profile of galunisertib plus TMZ/RTX regimen was consistent with previously published PK data of galunisertib. The overall safety profile across treatment arms was comparable. Conclusion No differences in efficacy, safety or pharmacokinetic variables were observed between the two treatment arms.

Background This phase I/II trial in patients with recurrent glioblastoma (GBM) evaluates the safety and preliminary efficacy of marizomib, an irreversible pan-proteasome inhibitor that crosses the blood–brain barrier. Methods Part A assessed the safety and efficacy of marizomib monotherapy. In Part B, escalating doses of marizomib (0.5–0.8 mg/m2) in combination with bevacizumab were evaluated. Part C explored intra-patient dose escalation of marizomib (0.8–1.0 mg/m2) for the combination. Results In Part A, 30 patients received marizomib monotherapy. The most common AEs were fatigue (66.7%), headache (46.7%), hallucination (43.3%), and insomnia (43.3%). One patient (3.3%) achieved a partial response. In Part B, the recommended phase II dose of marizomib was 0.8 mg/m2 when combined with bevacizumab 10 mg/kg. In Part C, dose escalation to 1.0 mg/m2 was not tolerated. Pooled analysis of 67 patients treated with marizomib ≤0.8 mg/m2 and bevacizumab showed a nonoverlapping safety profile consistent with the known safety profile of each agent: the most common grade ≥3 AEs were hypertension (16.4%), confusion (13.4%), headache (10.4%), and fatigue (10.4%). The overall response rate was 34.3%, including 2 patients with complete response. Six-month progression-free survival was 29.8%; median overall survival was 9.1 months. Conclusions The safety profile of marizomib as monotherapy and in combination with bevacizumab was consistent with previous observations that marizomib crosses the blood–brain barrier. Preliminary efficacy did not demonstrate a meaningful benefit of the addition of marizomib to bevacizumab for the treatment of recurrent GBM.

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.