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Purpose:To evaluate the results of the randomized, double-blind, placebo-controlled phase II clinical trial of ICT-107 in patients with newly diagnosed glioblastoma.Patients and Methods:We conducted a double-blinded randomized phase II trial of ICT-107 in newly diagnosed patients with glioblastoma (GBM) and tested efficacy, safety, quality of life (QoL), and immune response. HLA-A1+ and/or -A2+–resected patients with residual tumor ≤1 cm3 received radiotherapy and concurrent temozolomide. Following completion of radiotherapy, 124 patients, randomized 2:1, received ICT-107 [autologous dendritic cells (DC) pulsed with six synthetic peptide epitopes targeting GBM tumor/stem cell–associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL13Rα2] or matching control (unpulsed DC). Patients received induction ICT-107 or control weekly × 4 followed by 12 months of adjuvant temozolomide. Maintenance vaccinations occurred at 1, 3, and 6 months and every 6 months thereafter.Results:ICT-107 was well tolerated, with no difference in adverse events between the treatment and control groups. The primary endpoint, median overall survival (OS), favored ICT-107 by 2.0 months in the intent-to-treat (ITT) population but was not statistically significant. Progression-free survival (PFS) in the ITT population was significantly increased in the ICT-107 cohort by 2.2 months (P = 0.011). The frequency of HLA-A2 primary tumor antigen expression was higher than that for HLA-A1 patients, and HLA-A2 patients had higher immune response (via Elispot). HLA-A2 patients achieved a meaningful therapeutic benefit with ICT-107, in both the MGMT methylated and unmethylated prespecified subgroups, whereas only HLA-A1 methylated patients had an OS benefit.Conclusions:PFS was significantly improved in ICT-107–treated patients with maintenance of QoL. Patients in the HLA-A2 subgroup showed increased ICT-107 activity clinically and immunologically.

Purpose:Glioblastoma (GBM) is a heterogeneous malignancy with multiple subpopulations of cancer cells present within any tumor. We present the results of a phase I clinical trial using an autologous dendritic cell (DC) vaccine pulsed with lysate derived from a GBM stem-like cell line.Patients and Methods:Patients with newly diagnosed and recurrent GBM were enrolled as separate cohorts. Eligibility criteria included a qualifying surgical resection or minimal tumor size, ≤ 4-mg dexamethasone daily dose, and Karnofsky score ≥70. Vaccine treatment consisted of two phases: an induction phase with vaccine given weekly for 4 weeks, and a maintenance phase with vaccines administered every 8 weeks until depletion of supply or disease progression. Patients with newly diagnosed GBM also received standard-of-care radiation and temozolomide. The primary objective for this open-label, single-institution trial was to assess the safety and tolerability of the autologous DC vaccine.Results:For the 11 patients with newly diagnosed GBM, median progression-free survival (PFS) was 8.75 months, and median overall survival was 20.36 months. For the 25 patients with recurrent GBM, median PFS was 3.23 months, 6-month PFS was 24%, and median survival was 11.97 months. A subset of patients developed a cytotoxic T-cell response as determined by an IFNγ ELISpot assay.Conclusions:In this trial, treatment of newly diagnosed and recurrent GBM with autologous DC vaccine pulsed with lysate derived from an allogeneic stem-like cell line was safe and well tolerated. Clinical outcomes add to the body of evidence suggesting that immunotherapy plays a role in the treatment of GBM.

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Supplementary Data from A Phase I Study of Autologous Dendritic Cell Vaccine Pulsed with Allogeneic Stem-like Cell Line Lysate in Patients with Newly Diagnosed or Recurrent Glioblastoma

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Supplementary Figure from A Phase I Study of Autologous Dendritic Cell Vaccine Pulsed with Allogeneic Stem-like Cell Line Lysate in Patients with Newly Diagnosed or Recurrent Glioblastoma

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High grade gliomas are associated with poor prognosis and high mortality. Conventional treatments and management of high grade gliomas have shown little improvement in 5-year overall survival. This phase I trial evaluated the safety, immunogenicity, and potential synergy of surgical resection with Gliadel Wafer implantation, followed by autologous tumor lysate-pulsed dendritic cell (DC) vaccine in patients with malignant glioma. Primary end points of this study were safety and surrogate markers of immunogenicity, overall survival, and progression free survival. Following surgical resection, Gliadel Wafers were placed along the resection cavity. Patients subsequently received intradermal injections of autologous tumor lysate-pulsed DC vaccines 3 times at 2 week intervals. Treatment response was evaluated clinically and through MRI at regular intervals. Twenty-eight patients received Gliadel Wafers and DC vaccination: 11 newly diagnosed (8 glioblastoma [GBM], 2 anaplastic astrocytoma [AA], and 1 anaplastic oligodendroglioma [AO]) and 17 recurrent (15 GBMs, 1 AA, and 1 AO) high grade gliomas. Immunogenicity data was collected for 20 of the 28 patients. Five of 20 patients showed elevated IFN-γ responses following vaccination. Median progression-free survival and overall survival for all GBM patients in the trial from the start of vaccination were 3.6 months and 16.9 months respectively. Comparisons between vaccine responders and non-vaccine responders were not statistically significant. Adjuvant autologous dendritic cells pulsed with tumor-lysate following resection and Gliadel Wafer placement is safe, elicits modest immunogenicity and shows similar clinical outcomes in patients who had DC vaccination in previous studies.

Recurrent glioblastoma (GBM) is an aggressive disease with poor survival and limited treatment options. SL-701 is a novel immunotherapy comprised of synthetic peptides designed to elicit an anti-tumor immune response against GBM antigens IL-13Rα2, ephrinA2, and survivin. Here we describe an 18-color flow cytometry analysis from stage 2 of a Ph2 clinical trial of SL-701+poly-ICLC+bevacizumab (NCT02078648), in which 12-month overall survival (OS) was 50%. Of the 27 patients in stage 2, 24 (89%) developed heterogeneous T-cell responses against 1, 2, or 3 of the SL-701 CD8 peptides. Magnitude and kinetics of peptide responses were variable among these patients with no clear relationship to OS. Therefore, a phenotypic analysis of the T-cell response in all 27 patients was conducted using terraFlow, a unique data analysis approach utilizing machine learning to identify T-cell phenotypes associated with clinical response from all possible combinations of markers. In total, 10,184 unique SL-701 induced phenotypes were measured, including 223 phenotypes (P < 0.05) and 16 core phenotypes that uniquely represent differences between patients with OS above or below 12 months (P < 0.05). 50% of the core phenotypes were CD8+ CD57+ CD107a+ PD-1- SL-701-specific T-cells, which are highly-differentiated memory T-cells primed for cytotoxicity. The frequency of the CD57+ core phenotypes (8%-18%) was enhanced 1.6- to 2.3-fold in patients with an OS > 12 months (P < 0.05). Similarly, 2 core phenotypes identified cytotoxic CD4+ and CD8+ T cells, which were enhanced 1.9- and 2.5-fold in patients with an OS >12 months. The final 6 core phenotypes identified activated CD4+ CD154+ SL-701-specific T-cells (5%-19%) that were enhanced 0.3- to 0.5-fold in patients with an OS < 12 months (P < 0.05), suggesting helper T-cell responses in the absence of cytotoxic T-cell responses are associated with an OS < 12 months. Deep sequencing of SL-701-specific T-cells using whole transcriptome-based molecular cytometry is planned.

Purpose: Glioblastoma (GBM) is a heterogeneous malignancy with multiple subpopulations of cancer cells present within any tumor. We present the results of a phase I clinical trial using an autologous dendritic cell (DC) vaccine pulsed with lysate derived from a GBM stem-like cell line. Patients and Methods: Patients with newly diagnosed and recurrent GBM were enrolled as separate cohorts. Eligibility criteria included a qualifying surgical resection or minimal tumor size, ≤ 4-mg dexamethasone daily dose, and Karnofsky score ≥70. Vaccine treatment consisted of two phases: an induction phase with vaccine given weekly for 4 weeks, and a maintenance phase with vaccines administered every 8 weeks until depletion of supply or disease progression. Patients with newly diagnosed GBM also received standard-of-care radiation and temozolomide. The primary objective for this open-label, single-institution trial was to assess the safety and tolerability of the autologous DC vaccine. Results: For the 11 patients with newly diagnosed GBM, median progression-free survival (PFS) was 8.75 months, and median overall survival was 20.36 months. For the 25 patients with recurrent GBM, median PFS was 3.23 months, 6-month PFS was 24%, and median survival was 11.97 months. A subset of patients developed a cytotoxic T-cell response as determined by an IFNγ ELISpot assay. Conclusions: In this trial, treatment of newly diagnosed and recurrent GBM with autologous DC vaccine pulsed with lysate derived from an allogeneic stem-like cell line was safe and well tolerated. Clinical outcomes add to the body of evidence suggesting that immunotherapy plays a role in the treatment of GBM.

Background Gliosarcoma (GS) refers to the presence of mesenchymal differentiation (as seen using light microscopy) in the setting of glioblastoma (GB, an astrocytoma, WHO Grade 4). Although the same approach to treatment is typically adopted for GS and GB, there remains some debate as to whether GS should be considered a discrete pathological entity. Differences between these tumors have not been clearly established at the molecular level. Methods Patients with GS (n=48) or GB (n=1229) underwent molecular profiling (MP) with a pan-cancer panel of tests as part of their clinical care. The methods employed included next-generation sequencing (NGS) of DNA and RNA, copy number variation (CNV) of DNA and immunohistochemistry (IHC). The MP comprised 1153 tests in total, although results for each test were not available for every tumor profiled. We analyzed this data retrospectively in order to determine if our results were in keeping with what is known about the pathogenesis of GS by contrast with GB. We also sought novel associations between the MP and GS vs. GB which might improve our understanding of pathogenesis of GS. Results Potentially meaningful associations (pAll of the differences we observed have been associated with epithelial-to-mesenchymal transition (EMT) in other tumor types. Many of the changes we saw in GS are novel in the setting of glial tumors, including copy number amplification in LYL1 and mutations in PTPN11. Conclusions GS shows certain characteristics of EMT, by contrast with GB. Treatments targeting immuno-evasion may be of greater therapeutic value in GS relative to GB.

Purpose: To evaluate the results of the randomized, double-blind, placebo-controlled phase II clinical trial of ICT-107 in patients with newly diagnosed glioblastoma. Patients and Methods: We conducted a double-blinded randomized phase II trial of ICT-107 in newly diagnosed patients with glioblastoma (GBM) and tested efficacy, safety, quality of life (QoL), and immune response. HLA-A1+ and/or -A2+–resected patients with residual tumor ≤1 cm3 received radiotherapy and concurrent temozolomide. Following completion of radiotherapy, 124 patients, randomized 2:1, received ICT-107 [autologous dendritic cells (DC) pulsed with six synthetic peptide epitopes targeting GBM tumor/stem cell–associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL13Rα2] or matching control (unpulsed DC). Patients received induction ICT-107 or control weekly × 4 followed by 12 months of adjuvant temozolomide. Maintenance vaccinations occurred at 1, 3, and 6 months and every 6 months thereafter. Results: ICT-107 was well tolerated, with no difference in adverse events between the treatment and control groups. The primary endpoint, median overall survival (OS), favored ICT-107 by 2.0 months in the intent-to-treat (ITT) population but was not statistically significant. Progression-free survival (PFS) in the ITT population was significantly increased in the ICT-107 cohort by 2.2 months (P = 0.011). The frequency of HLA-A2 primary tumor antigen expression was higher than that for HLA-A1 patients, and HLA-A2 patients had higher immune response (via Elispot). HLA-A2 patients achieved a meaningful therapeutic benefit with ICT-107, in both the MGMT methylated and unmethylated prespecified subgroups, whereas only HLA-A1 methylated patients had an OS benefit. Conclusions: PFS was significantly improved in ICT-107–treated patients with maintenance of QoL. Patients in the HLA-A2 subgroup showed increased ICT-107 activity clinically and immunologically.

The world of molecular profiling has undergone revolutionary changes over the last few years as knowledge, technology, and even standard clinical practice have evolved. Broad molecular profiling is now nearly essential for all patients with metastatic solid tumors. New agents have been approved based on molecular testing instead of tumor site of origin. Molecular profiling methodologies have likewise changed such that tests that were performed on patients a few years ago are no longer complete and possibly inaccurate today. As with all rapid change, medical providers can quickly fall behind or struggle to find up‐to‐date sources to ensure he or she provides optimum care. In this review, the authors provide the current state of the art for molecular profiling/precision medicine, practice standards, and a view into the future ahead.

Importance Clinical outcomes for glioblastoma remain poor. Treatment with immune checkpoint blockade has shown benefits in many cancer types. To our knowledge, data from a randomized phase 3 clinical trial evaluating a programmed death-1 (PD-1) inhibitor therapy for glioblastoma have not been reported. Objective To determine whether single-agent PD-1 blockade with nivolumab improves survival in patients with recurrent glioblastoma compared with bevacizumab. Design, Setting, and Participants In this open-label, randomized, phase 3 clinical trial, 439 patients with glioblastoma at first recurrence following standard radiation and temozolomide therapy were enrolled, and 369 were randomized. Patients were enrolled between September 2014 and May 2015. The median follow-up was 9.5 months at data cutoff of January 20, 2017. The study included 57 multicenter, multinational clinical sites. Interventions Patients were randomized 1:1 to nivolumab 3 mg/kg or bevacizumab 10 mg/kg every 2 weeks until confirmed disease progression, unacceptable toxic effects, or death. Main Outcomes and Measures The primary end point was overall survival (OS). Results A total of 369 patients were randomized to nivolumab (n = 184) or bevacizumab (n = 185). TheMGMTpromoter was methylated in 23.4% (43/184; nivolumab) and 22.7% (42/185; bevacizumab), unmethylated in 32.1% (59/184; nivolumab) and 36.2% (67/185; bevacizumab), and not reported in remaining patients. At median follow-up of 9.5 months, median OS (mOS) was comparable between groups: nivolumab, 9.8 months (95% CI, 8.2-11.8); bevacizumab, 10.0 months (95% CI, 9.0-11.8); HR, 1.04 (95% CI, 0.83-1.30);P = .76. The 12-month OS was 42% in both groups. The objective response rate was higher with bevacizumab (23.1%; 95% CI, 16.7%-30.5%) vs nivolumab (7.8%; 95% CI, 4.1%-13.3%). Grade 3/4 treatment-related adverse events (TRAEs) were similar between groups (nivolumab, 33/182 [18.1%]; bevacizumab, 25/165 [15.2%]), with no unexpected neurological TRAEs or deaths due to TRAEs. Conclusions and Relevance Although the primary end point was not met in this randomized clinical trial, mOS was comparable between nivolumab and bevacizumab in the overall patient population with recurrent glioblastoma. The safety profile of nivolumab in patients with glioblastoma was consistent with that in other tumor types. Trial Registration ClinicalTrials.gov Identifier:NCT02017717

Treatment of glioblastoma (GBM) remains a critical challenge and unmet medical need due to limited treatment options. SL-701 is a novel immunotherapy comprised of synthetic peptides designed to elicit a target-specific anti-tumor immune response against the GBM antigens IL-13Rα2, ephrinA2, and survivin. A multicenter, 2-stage, phase 2 clinical trial (NCT02078648) that evaluated the safety and efficacy of SL-701 in 74 adults with recurrent GBM was previously reported. This report describes preliminary data to suggest a correlation of immunocompetence to clinical outcome. In stage 2 (SL-701 + bevacizumab + poly-ICLC) the overall survival at 12 months was 50%. Two of 28 patients enrolled in stage 2 achieved CR (duration of response: 7.8 and 8.8 months) and 2 achieved PR (duration of response: 7.9 and 8.8 months). In a preliminary analysis to assess CD8+ T-cell responses, long-term survivors were comprised largely of subjects with an SL-701-induced target-specific CD8+ T-cell response, indicating a potential correlation of immunocompetence to clinical outcome. By week 24, SL-701-induced target-specific CD8+ T cells expressing IFNg were detected in 8 of 27 patients (30%) who had sufficient samples, with co-expression of PD-1, TIM3, and LAG3 detected in 4 patients. To further understand the T-cell response to SL-701, deep sequencing of target-specific CD8+ T cells using whole transcriptome-based molecular cytometry and high parameter (25+ color) flow cytometry is currently underway and updated data will be reported.

BACKGROUND Optimal management of progressive high-grade gliomas (HGG) is not fully defined and outcomes are poor. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme which converts tryptophan to kynurenines, which contribute to the immunosuppresive tumor microenvironment (TME). Targeting the TME by inhibiting IDO1 is a strategy for potential improvement in survival in HGG. METHODS A phase 1/2 trial using the IDO1 inhibitor indoximod was conducted in progressive grade 3 and 4 gliomas. The phase 1 cmponent used a 3 + 3 design escalating indoximod from 600mg po BID to 1200mg po BID in conjunction with temozolomide (150 mg/m2, 5/28 days). The phase 2 component consisted of 3 cohorts: A) indoximod+temozolomide B) indoximod+temozolomide+bevacizumab (patients already on bevacizumab) C) indoximod+temozolomide+stereotactic radiosurgery (SRS). Patients were treated until progression or toxicity. RESULTS 33.3% of patients developed indoximod TEAEs. There were no dose limiting toxicities in the phase 1 component (n=12). 1200 mg BID was established as the phase 2 dose of indoximod. In the phase 2 component (n=148) PFS6 was 74% (A), 93% (B), 70% (C). Median OS was 289 days [10.3 months](A), 159 days [5.7 months](B), 285 days [10.2 months](C). Correlative study results will be available for meeting presentation. CONCLUSIONS The IDO1 inhibitor indoximod proved safe and tolerable in conjunction with temozolomide, bevacizumab, and SRS in patients with progressive HGG. There was a trend toward better survival outcomes when indoximod was combined with temozolomide alone or temozolomide+SRS.

INTRODUCTION There is abundant interest in the potential therapeutic and supportive role of a ketogenic diet (KD) for glioblastoma patients. We conducted a single-arm phase 1 trial to assess the safety and feasibility of KD plus standard-of-care (SOC) in glioblastoma patients (NCT03451799). METHODS Adults within 3 months of diagnosis participated in a 16-week intervention of a classic 3:1 KD (grams fat : grams carbohydrate + protein) with dietitian support. Blood glucose and ketone levels were assessed twice daily (Keto-Mojo), with remote monitoring of daily weight and activity (Fitbit). The primary objective was to assess safety (weight stability, CTCAE) and feasibility (maintaining ketosis > 0.3mM for > 50% of study period). Secondary objectives included assessments of progression-free survival (PFS), overall survival (OS), health-related quality of life (HRQOL), and cognition (MoCA). RESULTS From 04/2018-02/2021, 14 patients were evaluable: female:male, 8:6, median age 55 years, KPS 80, BMI 24.5. MGMT promoter methylation: 6 present, 7 absent, 1 indeterminate. Adherence to KD was high, with all patients maintaining ketosis ( > 0.3mM) > 50% and 11 patients maintaining ketosis > 85% of study days. Adverse events (> Grade 2) potentially attributable to KD: appetite loss (Grade 2: 2); fatigue (Grade 2: 5); flu-like symptoms (Grade 2: 1); constipation (Grade 2: 5, Grade 3: 1). No patients were removed from study for safety reasons. HRQOL was stable, with improvements in role function (not statistically significant). MoCA score improved in 10/14 patients. Median PFS and OS from KD initiation were 11.7 and 29.1 months, respectively. CONCLUSION Our findings suggest that a supervised KD plus SOC is safe and feasible in glioblastoma patients. KD was well-tolerated with encouraging trends in HRQOL and cognition. PFS and OS in this small trial compare favorably to historical control. A multicenter phase 2 trial powered to assess efficacy is planned.

Mutations in the histone genes H3.3 and H3.1 are driver events in pediatric and adult gliomas and carry diagnostic and prognostic importance for tumors originating from midline structures. Patients with tumors affected by these mutations are difficult to treat. We surveyed a large cohort of gliomas for H3-mutations, including H3K27m. Consecutive gliomas submitted for tumor profiling at Caris Life Sciences from 2015- 2019 were analyzed. NextGen sequencing was done on 592 genes; MGMT promoter methylation was tested by pyrosequencing; and EGFRvIII and gene fusions were tested by RNA-sequencing. Of nearly 1800 tumors analyzed, 41 harbored H3F3A alterations, including 33 with the K27M mutation (4 arose from the spinal cord, 1 from cerebellum, 1 from brain stem, 4 from thalamus, and 23 from brain, NOS). Eight G34R mutations were identified. A HIST1H3B-K27M was detected in a tumor from the brain stem. H3 mutations were more prevalent in pediatric tumors, and all H3 mutations seen in pediatric tumors were from grade IV tumors. Among the H3-mutated adult tumors, histology differed. There were 2 grade II tumors, 1 low grade glioma, 1 anaplastic ganglioglioma, and 2 anaplastic astrocytomas. In the investigated cohort, H3-mutations were mutually exclusive of IDH1/2 mutations and EGFR alterations. Significantly higher mutation rates were seen in H3-mutated tumors for TP53, ATRX, NF1, PDGFRA, FGFR1, FBXW7, BLM, and TSC2 compared with H3-WT. The H3-WT tumors were more enriched for MGMT-methylation and PTEN mutation. In H3-mutated tumors that were MGMT-methylated, most H3-mutations seen were G34R while K27M was largely exclusive. There was a heterogeneous distribution of H3 mutations, and the co-occurring molecular alterations seen in H3-mutated tumors further support the hypothesis that these tumors are a distinct molecular entity. By better characterizing these associations, we can develop insight into novel treatment strategies for a class of tumors with historically dismal prognosis.

INTRODUCTION BRAF is a RAF-family kinase that regulates MAPK/ERK signaling. Activating BRAF mutations, including V600E, are common in circumscribed low-grade gliomas of childhood and young adulthood, but are uncommon in infiltrative astrocytomas, including glioblastoma. Their role in glioblastoma initiation and progression requires analysis of large datasets given the low frequency (1.0%) in TCGA IDH-wild-type glioblastomas. METHODS Molecular profiling was done on 4679 FFPE gliomas by next-generation sequencing at Caris Life Sciences, of which 3170 underwent RNA-sequencing for gene fusion and 4603 DNA-sequencing for mutations. MGMT promoter methylation was tested by pyrosequencing and PD-L1 IHC was performed using the SP142 clone. RESULTS Excluding variants of uncertain significance, BRAF mutations/fusions were most common in pleomorphic xanthoastrocytoma (PXA; N=12/24, 50%), glioneuronal tumors (N=6/13, 46%), pilocytic astrocytoma (PA; N=15/48, 31%), and ganglioglioma (n=5/18, 28%). BRAF fusions were uncommon (N=17), most frequent in PA (N=8/31, 26%) where they were associated with older age at daignosis (P=0.043), and typically involved KIAA1549 as fusion partner (70%). BRAF-mutated/fused glioblastoma patients (N=59/3126, 2%) were younger than BRAF-wild-type glioblastoma patients (54 versus 59 years, P=3.5x10-3); more likely to be MGMT-unmethylated (75% versus 56%, P=5.0x10-3); and 3x more likely to express PD-L1 (55% versus 17%, P=2.1x10-10). In tumors harboring a V600E mutation, the variant allele frequency (VAF) was similar in glioblastoma as in PXA, PA, ganglioglioma, and glioneuronal tumors (median VAF=35%). CONCLUSIONS BRAF-mutated glioblastoma were 3x more likely to express PD-L1 than BRAF-wild-type glioblastoma. We observed no differences in BRAF V600E clonality in BRAF-mutated glioblastoma compared to BRAF-mutated PXA, PA, ganglioglioma, and glioneuronal tumors, suggesting BRAF mutation is an initiating event in the clonal evolution of a subset of glioblastoma. There is rationale to evaluate combined BRAF inhibition with checkpoint inhibition in BRAF-mutated glioblastoma, potentially synergizing the complete response profile of the former with the durable response profile of the latter.

BACKGROUND: Gliosarcoma (GS) accounts for approximately 2% of WHO grade 4 gliomas and have a worse prognosis relative to glioblastoma (GBM). Epithelial-to-mesenchymal transition (EMT) is well recognized in a variety of tumors of ectodermal lineage. MATERIALS AND METHODS: Patients diagnosed with either a GS (n = 44) or GBM (n = 1449) underwent comprehensive molecular profiling including immunohistochemistry (IHC) and sequencing (DNA, RNA, pyrosequencing and fragment analysis). Statistical significance using Fisher’s exact test was set at p < 0.1 as this is exploratory work; no correction was made for multiple comparisons. RESULTS: The following were identified as enriched in GS based on the odds ratios (OR): CALR (copy number variation, CNV; OR= infinite; p = 0.032), LYL1 (CNV; OR=30; p=0.064); NTRK1 (fusion, RNAseq; OR= 30; p=0.063), IDH2 (mutation; OR=28; p=0.068), PTPN11 (mutation; OR=3; p=0.08), NF1 (mutation; OR=2.3; p=0.02; PD-L1 (IHC; OR=2.2; p=0.002); PD-1 (IHC; OR=1.6; p=0.0078). In contrast, the following were more common in GBM: EGFRvIII (fusion, RNAseq; OR=0.28; p=0.031); EGFRvIII (fragment analysis; OR=0.2; p=0.062); EGFR (CNV; OR=0.2; p=0.00083; IDH1 (mutation; OR=0; p=0.045) and EGFR (mutation; OS=0; p=0.012). Alterations with p>=0.1 are not reported here. CONCLUSIONS: Our study identified enriched markers in GS that have been associated with EMT in other tumor types. These findings are hypothesis generating and suggest that GS may be an example of EMT in GBM. The gene amplification in CALR and LYL1 has not been previously described. Higher levels of PD-1 and PD-L1 expression suggest that these may be targets of particular therapeutic importance in GS relative to GBM.

BACKGROUND: PD-1 and PD-L1 expression has not been well-described in PCNSL. In one report of 20 PCNSL tumors, PD-1 and PD-L1 expression on tumor cells (TC), tumor-infiltrating lymphocytes (TIL), or tumor-associated macrophages (TAM) was seen in 90% (Clin Neuropathol 2014;PMID:24359606). Another report of 4 patients with relapsed PCNSL showed clinical and radiographic responses to PD-1 blockade (Blood 2017;PMID:28356247). METHODS: Samples from 36 subjects with large B-cell PCNSL submitted to Caris Life Sciences from 20132018 were tested by NextGen Sequencing (NGS, 592-gene panel [n=30] or 45-gene panel [n=6]) for mutations and gene amplification. RNA sequencing (Archer FusionPlex) was used to detect gene fusions. TMB was calculated using somatic nonsynonymous missense mutation, and microsatellite instability (MSI) was tested by NGS. PD-L1 IHC (SP142) was tested on tumor cells and PD-1 was determined on TIL. RESULTS: High PD-L1 expression (>5% staining) was seen in 14 cases (39%), and low expression (15% staining) was noted in 11 cases (31%). Another 11 cases (30%) showed absent PD-L1 expression. PD-1 expression (>1 cell/high-power field) was seen in 10/12 tumors (83%) without correlation with PD-L1. TMB of 5 mutations per megabase (mt/MB) was seen in all 30 tumors tested with the 592-gene panel, with 27% (n=8) exhibiting high TMB (17 mt/MB). No samples had high level MSI. Overall, 18/30 tumors (60%) had high PD-L1 or high TMB. Mutations in 25 genes were seen; the most frequent were MYD88 (26/30, 87%, all L265P), PIM1 (16/30, 60%), and CD79B (15/30, 50%, all Y196). Among 7 cases tested with RNA-sequencing, one recently reported ETV6-IGH fusion was found (Neuro-Oncology 2018;PMID:29432597). CONCLUSIONS: We found high TMB and PD-L1 expression in PCNSL with no correlation. Nearly two thirds of PCNSL tumors harbor favorable biomarker profiles with anticipated responsiveness to checkpoint inhibitors. Further studies are needed to validate initial results.

Objective: A subset of meningiomas recur after surgery and radiation therapy, but no medical therapy for recurrent meningioma has proven effective. Methods: Pasireotide LAR is a long-acting somatostatin analog that may inhibit meningioma growth. This was a phase II trial in patients with histologically confirmed recurrent or progressive meningioma designed to evaluate whether pasireotide LAR prolongs progression-free survival at 6 months (PFS6). Patients were stratified by histology (atypical [World Health Organization grade 2] and malignant [grade 3] meningiomas in cohort A and benign [grade 3] in cohort B). Results: Eighteen patients were accrued in cohort A and 16 in cohort B. Cohort A had median age 59 years, median Karnofsky performance status 80, 17 (94%) had previous radiation therapy, and 11 (61%) showed high octreotide uptake. Cohort B had median age 52 years, median Karnofsky performance status 90, 11 (69%) had previous radiation therapy, and 12 (75%) showed high octreotide uptake. There were no radiographic responses to pasireotide LAR therapy in either cohort. Twelve patients (67%) in cohort A and 13 (81%) in cohort B achieved stable disease. In cohort A, PFS6 was 17% and median PFS 15 weeks (95% confidence interval: 8–20). In cohort B, PFS6 was 50% and median PFS 26 weeks (12–43). Treatment was well tolerated. Octreotide uptake and insulin-like growth factor–1 levels did not predict outcome. Expression of somatostatin receptor 3 predicted favorable PFS and overall survival. Conclusions: Pasireotide LAR has limited activity in recurrent meningiomas. The finding that somatostatin receptor 3 is associated with favorable outcomes warrants further investigation. Classification of evidence: This study provides Class IV evidence that in patients with recurrent or progressive meningioma, pasireotide LAR does not significantly increase the proportion of patients with PFS at 6 months.

Background: Multiple radiation-induced cavernous malformations of the cauda equina are extremely rare. A review of the literature suggested that the post-irradiation lumbosacral radiculopathy in our patient was most likely associated with a diagnosis of multiple radiation-induced cavernous malformations of the cauda equina. Case Description: A 76-year-old man with a remote history of abdominal radiation therapy presented with a 6-month history of progressively worsening right foot drop and balance impairment. Magnetic resonance imaging (MRI) revealed multiple enhancing areas of the cauda equina concerning for carcinomatous meningitis, however, cerebrospinal fluid (CSF) analysis was unrevealing. Intraoperative findings were consistent with multiple radiation-induced cavernous malformations of the cauda equina. Conclusions: Multiple radiation-induced cavernous malformations of the cauda equina may mimic carcinomatous or infectious meningitis. Clinicians should be suspicious of this diagnosis when CSF and MRI findings are inconsistent with metastatic disease or infectious meningitis in patients who present with radiculopathy and a history of radiation therapy.

Treatment options are limited for recurrent glioblastoma (GBM). Verubulin is a microtubule destabilizer and vascular disrupting agent that achieve high brain concentration relative to plasma in animals. Adults with recurrent GBM who failed prior standard therapy were eligible. The primary endpoint was 1-month progression-free survival (PFS-1) for bevacizumab refractory (Group 2) and 6-month progression-free survival (PFS-6) for bevacizumab naive patients (Group 1). Verubulin was administered at 3.3 mg/m2 as a 2-h intravenous infusion once weekly for 3 consecutive weeks in a 4-week cycle. The planned sample size was 34 subjects per cohort. 56 patients (37 men, 19 women) were enrolled, 31 in Group 1 and 25 in Group 2. The PFS-6 for Group 1 was 14 % and the PFS-1 for Group 2 was 20 %. Median survival from onset of treatment was 9.5 months in Group 1 and 3.4 months in Group 2. Best overall response was partial response (n = 3; 10 % in Group 1; n = 1; 4.2 % in Group 2) and stable disease (n = 7; 23 % in Group 1; n = 5; 21 % in Group 2). In Group 1, 38.7 % of patients experienced a serious adverse event; however only 3.2 % were potentially attributable to study drug. In Group 2, 44 % of patients experienced a serious adverse event although none were attributable to study drug. Accrual was terminated early for futility. Single agent verubulin, in this dose and schedule, is well tolerated, associated with moderate but tolerable toxicity but has limited activity in either bevacizumab naive or refractory recurrent GBM.

BACKGROUND: Gliosarcomas (GS) are rare histological glioblastoma (GB) variants with glial and mesenchymal components. GS has been reported to have a similar genetic profile to primary GB. In a small series of GS, tissue from both the glial and sarcomatous components revealed PTEN and TP53 mutations, and p16 deletion in both tissue components. Studies on systematic comparison of GS and GB are scarce. MATERIAL AND METHODS: A total of 44 GS and 1449 GB tumors profiled by Caris Life Sciences from 2013 to 2017 were tested by NextGen sequencing (NGS, 592 or 45 gene panels) for mutations and gene amplification. Tumor mutational burden (TMB) was calculated using somatic nonsynonymous missense mutations. Microsatellite instability (MSI) was tested by NGS. PD-L1 immunohistochemistry (SP142) was done on tumor cells and PD-1 on tumor-infiltrating lymphocytes. MGMT promoter methylation was tested by pyrosequencing; EGFRvIII and gene fusions by RNA-sequencing (ArcherDx FusionPlex). RESULTS: Mutations in 16 genes were seen in GS: the most frequent were TP53 (41 %), NF1 (33 %), PTEN (29 %), RB1 (10%), PTPN11 (7%) and PIK3CA (5%). Amplification of CDK4 (8%), MET (8%) and MDM2 (4%) were seen and NTRK1 fusion was seen in 1 of 20 (5%) GS tumors tested with RNA-SEQ. When compared to GB, GS had significantly higher NF1 (GS: 33% vs. GB 14%, p = 0.008) and PTPN11 (7% vs. 2%, p = 0.04) mutations. Furthermore, immune-associated markers: PD-L1 (38.5% vs. 16.3%, p = 0.0003), PD-1 (75% vs. 49.2%, p = 0.01) and MSI-High (3.8 vs. 0.5%, p = 0.038) were significantly higher in GS; TMB-High (> = 17mut/MB) (7.7 vs. 2.9%, p = 0.17) showed a trend. In contrast, EGFR alterations including EGFR amplification (7.7 & 37.2%, p = 0.0021) and EGFR mutations (0 vs. 11%, p = 0.02) were less prevalent in GS than GB as also EGFRvIII (5.9 vs. 18.9%, p = 0.055), EGFR fusions (0 vs. 9%, p > 0.05), IDH1 mutation (0 vs. 7.8%, p = 0.054) and MGMT promoter methylation (34.1 & 45%, p > 0.05). CONCLUSION: In summary, based on our analysis, GS appears to be a distinct biological entity with unique genomic features and immunophenotype compared to GB. These results also provide insight into potential immune therapy, based on the association of PD-1/PD-L1 with other key genetic alterations in this population, which warrants further investigation in clinical studies.

BACKGROUND Current therapies for recurrent glioblastoma provide limited survival benefit. In the open-label, phase 3 CheckMate 143 study (NCT02017717), although the primary endpoint was not met, the median overall survival (mOS) was comparable between nivolumab (anti–PD-1) and bevacizumab in the overall population of patients with glioblastoma at first recurrence after temozolomide chemoradiotherapy (Reardon et al, WFNOS 2017). Exploratory subgroup analyses were conducted to evaluate the association of O-6-methylguanine DNA methyltransferase (MGMT) promoter methylation status and corticosteroid use at baseline with mOS. METHODS Prespecified patient subgroups included MGMT promoter status (methylated vs unmethylated) and baseline corticosteroid use (yes [within 5 days of first dose] vs no). FINDINGS: Methylation status was available for 102/184 (55%) nivolumab-treated and 109/185 (59%) bevacizumab-treated patients. Using a multivariable Cox proportional hazards model analysis, no baseline corticosteroid use (HR, 0.59 [95% CI, 0.36–0.95]) and methylated MGMT status (HR, 0.47 [95% CI, 0.29–0.78]) were each associated with longer mOS among nivolumab-treated patients. Among patients with methylated MGMT and no baseline corticosteroid use, mOS was 17.0 months with nivolumab (n=31) and 10.1 months with bevacizumab (n=22; HR, 0.58 [95% CI, 0.30–1.11]). In patients with methylated tumors and baseline corticosteroids, mOS was 7.7 months with nivolumab (n=12) and 13.5 months with bevacizumab (n=17). Among patients with unmethylated tumors and no baseline corticosteroids, mOS was 8.3 months with nivolumab (n=30) and 10.3 months with bevacizumab (n=29). In patients with unmethylated tumors and baseline corticosteroids, mOS was 5.6 months with nivolumab (n=28) and 8.3 months with bevacizumab (n=28). CONCLUSION A trend toward longer mOS with nivolumab was observed in a subgroup of patients with methylated MGMT and no baseline corticosteroid use. These findings suggest that MGMT methylation status and corticosteroid use at baseline could be used to identify patients who may benefit from nivolumab and thus warrant further study.

e13540 Background: Mutations in the histone genes H3.3 and H3.1 are driver events in pediatric and adult gliomas and carry diagnostic and prognostic importance for tumors originating from midline structures. Patients with tumors affected by these mutations are notoriously difficult to treat, and the prevalence and molecular correlates of H3 mutations in a large glioma population have not been systematically reported. We aim to survey a large cohort of gliomas for H3-mutations. Methods: Consecutive gliomas submitted for tumor profiling at Caris Life Sciences from 2015- 2018 were analyzed. NextGen sequencing was done on 592 genes (NextSEQ Illumina); MGMT promoter methylation was tested by pyrosequencing; and EGFRvIII and gene fusions were tested by RNA-sequencing (ArcherDx FusionPlex). Results: Of the 1763 tumors analyzed, 41 harbored H3F3A alterations, including 33 with the K27M mutation (4 arose from the spinal cord, 1 from cerebellum, 1 from brain stem, 4 from thalamus, and 23 from brain, NOS). Eight G34R mutations were identified. A HIST1H3B-K27M was detected in a tumor from the brain stem. Overall, H3 mutations were more prevalent in pediatric tumors (8 of 26, 31%) than adult tumors (34 of 1737, 2%). All H3 mutations seen in pediatric tumors were from grade IV tumors. Among the 34 H3-mutated adult tumors, histology differed. There were 2 grade II tumors (diffuse astrocytoma), 1 low grade glioma from the spinal cord, 1 anaplastic ganglioglioma and 2 anaplastic astrocytomas. In the investigated cohort, H3-mutations were mutually exclusive of IDH1/2 mutations and EGFR alterations. Significantly higher mutation rates were seen in H3-mutated tumors for TP53 (69%. Vs. 37%), ATRX (46% vs. 24%), NF1 (23% vs. 12%) , PDGFRA (17% vs. 1%), FGFR1 (12% vs. 1%), FBXW7 (5% vs. 0), BLM (3% vs. 0) and TSC2 (2% vs.0) compared with H3-WT (p < 0.05). The H3-WT tumors were more enriched for MGMT-methylation (53% vs. 26%) and PTEN mutation (22% vs. 7%) (p < 0.05). In H3-mutated tumors that were MGMT-methylated (n = 10), most H3-mutations seen were G34R (n = 8) while K27M (n = 2) was largely exclusive. Conclusions: This survey of a large cohort of gliomas revealed a heterogeneous distribution of H3 mutations. The co-occurring molecular alterations seen in H3-mutated tumors further support the hypothesis that these tumors are a distinct molecular entity. By better characterizing these associations, we are closer to developing more insight into novel treatment strategies for a class of tumors with historically dismal prognosis.

Background. The signal transduction pathways of epidermal growth factor receptor and Ras are both important in the growth of glioblastoma multiforme (GBM). We hypothesized that inhibition of both pathways would improve the survival time of patients with recurrent GBM. Methods. Patients with recurrent/progressive GBM with 0–2 prior chemotherapy regimens received erlotinib 150 mg once daily and sorafenib 400 mg twice daily until progression. The primary endpoint was overall survival. Pharmacokinetic sampling was performed during cycle 1. Results. The median overall survival was 5.7 months. Progression-free survival at 6 months was 14%. Toxicity was manageable. Clearance of erlotinib was markedly enhanced by sorafenib. Conclusion. The study did not meet its objective of a 30% increase in overall survival time compared with historical controls. Erlotinib and sorafenib have significant pharmacokinetic interactions that may negatively impact the efficacy of the combination regimen.

Purpose A randomized, phase III, placebo-controlled, partially blinded clinical trial (REGAL [Recentin in Glioblastoma Alone and With Lomustine]) was conducted to determine the efficacy of cediranib, an oral pan–vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma. Patients and Methods Patients (N = 325) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 2:2:1 to receive (1) cediranib (30 mg) monotherapy; (2) cediranib (20 mg) plus lomustine (110 mg/m2); (3) lomustine (110 mg/m2) plus a placebo. The primary end point was progression-free survival based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted magnetic resonance imaging (MRI) brain scans. Results The primary end point of progression-free survival (PFS) was not significantly different for either cediranib alone (hazard ratio [HR] = 1.05; 95% CI, 0.74 to 1.50; two-sided P = .90) or cediranib in combination with lomustine (HR = 0.76; 95% CI, 0.53 to 1.08; two-sided P = .16) versus lomustine based on independent or local review of postcontrast T1-weighted MRI. Conclusion This study did not meet its primary end point of PFS prolongation with cediranib either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma, although cediranib showed evidence of clinical activity on some secondary end points including time to deterioration in neurologic status and corticosteroid-sparing effects.

MEDI-575, an immunoglobulin G2κ monoclonal antibody, selectively binds to platelet-derived growth factor-α receptor (PDGFR-α) with high specificity. This multicenter, single-arm, open-label, phase II study evaluated the efficacy and safety of MEDI-575 in patients with recurrent glioblastoma. Adults with first recurrence of glioblastoma following surgery, temozolomide, and radiation received MEDI-575 25 mg/kg intravenously over 60 min every 21 days until disease progression or unacceptable toxicity. Six-month progression-free survival rate (PFS-6) was the primary end point; secondary measures included response rate, overall survival (OS), and safety/tolerability. PDGFR-α expression was evaluated by immunohistochemistry. Fifty-six patients were enrolled; median age was 56.5 years (range 23–79), 66 % were male, and 66 % were aged ≥65 years. PFS-6 was 15.4 % [90 % confidence interval (CI) 8.1–24.9]. No complete or partial responses were observed; 23 (41.1 %) patients had stable disease as best response. Median PFS was 1.4 months (90 % CI 1.4, 1.8); median OS was 9.7 months (90 % CI 6.5, 11.8). The most common treatment-related adverse events (AEs) were diarrhea (16 %), nausea (13 %), and fatigue (13 %). Twelve (21 %) patients reported grade ≥3 AEs, with hydrocephalus (n = 3), dysphagia (n = 2), and convulsion (n = 2) reported in more than 1 patient. Two patients had treatment-related Grade ≥3 AEs of decreased lymphocyte count and asthenia (n = 1 each). Seven patients (13 %) discontinued MEDI-575 owing to AEs. Labeling of PDGFRα in glioblastoma cells and tumor-associated stromal cells was highly variable, with no correlation with PFS. MEDI-575, although well tolerated, had limited clinical activity in recurrent glioblastoma.

Cediranib is an orally available, pan-VEGFR tyrosine kinase inhibitor. A previous Phase III study of patients with recurrent glioblastoma treated with this drug did not meet the primary end of progressive-free survival (PFS). We identified one patient, a 57-year-old Caucasian female who, following surgery in October 2008 and concurrent temozolomide and radiation therapy from November 8, 2008, to January 6, 2009, developed a tumor progression of the left posterior frontal measuring 1.2 x 1.5 cm in February 2009. She was enrolled in a randomized, Phase III, placebo-controlled, partially-blinded clinical trial of cediranib as either monotherapy or in combination with lomustine (CCNU) versus CCNU. She was randomized to receive a combination therapy with 1st cycle CCNU 190 mg and cediranib 20 mg per day on April 15, 2009. However, she developed nephrotic syndrome and uncontrolled hypertension and was taken off this study in May 2010. Her six-week MRI showed a 50% tumor regression and a complete response at twenty-four weeks. With no enhancement seen on MRI on June 4, 2015, she has been off therapy and in clinical remission over five years with high functional level and good quality of life (KPS-90%). This is a case report of successful therapy for recurrent glioblastoma with long-term remission despite termination of therapy greater than six years from cediranib and limited CCNU dosage.

Background This study evaluated the safety and immune responses to an autologous dendritic cell vaccine pulsed with class I peptides from tumor-associated antigens (TAA) expressed on gliomas and overexpressed in their cancer stem cell population (ICT-107). Methods TAA epitopes included HER2, TRP-2, gp100, MAGE-1, IL13Rα2, and AIM-2. HLA-A1- and/or HLA-A2-positive patients with glioblastoma (GBM) were eligible. Mononuclear cells from leukapheresis were differentiated into dendritic cells, pulsed with TAA peptides, and administered intradermally three times at two-week intervals. Results Twenty-one patients were enrolled with 17 newly diagnosed (ND-GBM) and three recurrent GBM patients and one brainstem glioma. Immune response data on 15 newly diagnosed patients showed 33 % responders. TAA expression by qRT-PCR from fresh-frozen tumor samples showed all patient tumors expressed at least three TAA, with 75 % expressing all six. Correlations of increased PFS and OS with quantitative expression of MAGE1 and AIM-2 were observed, and a trend for longer survival was observed with gp100 and HER2 antigens. Target antigens gp100, HER1, and IL13Rα2 were downregulated in recurrent tumors from 4 HLA-A2+ patients. A decrease in or absence of CD133 expression was seen in five patients who underwent a second resection. At a median follow-up of 40.1 months, six of 16 ND-GBM patients showed no evidence of tumor recurrence. Median PFS in newly diagnosed patients was 16.9 months, and median OS was 38.4 months. Conclusions Expression of four ICT-107 targeted antigens in the pre-vaccine tumors correlated with prolonged overall survival and PFS in ND-GBM patients. The goal of targeting tumor antigens highly expressed on glioblastoma cancer stem cells is supported by the observation of decreased or absent CD133 expression in the recurrent areas of gadolinium-enhanced tumors.

Sorafenib is an inhibitor of multiple kinases that has demonstrated antiproliferative and antiangiogenic activity in a number of in vitro and in vivo model systems. A phase I study was conducted to determine the maximum tolerated dose (MTD) of sorafenib in patients with recurrent malignant glioma. Sorafenib was given orally, twice a day (BID), continuously in 28-day cycles. The dose was escalated in 2 groups of patients stratified by use of enzyme-inducing antiseizure drugs (± EIASDs). Dose-limiting toxicity (DLT) was defined as any grades 3-4 nonhematological toxicity, grade 4 hematological toxicity, and febrile neutropenia. The number of evaluable patients enrolled in the +EIASD and -EIASD arms were 23 and 24, respectively. DLTs were predominantly dermatological and gastrointestinal effects, as observed in previous clinical trials of sorafenib. The MTD was 600 mg BID for patients receiving EIASDs and 800 mg BID for those who were not. The plasma pharmacokinetics of sorafenib were not significantly affected by the concurrent administration of EIASDs. The MTD of sorafenib given orally BID on a continuous basis was established as 600 mg BID in patients with malignant glioma who were concurrently receiving EIASDs and 800 mg BID in those who were not. Further evaluation is warranted of sorafenib at the recommended MTD against recurrent or progressive malignant glioma in combination with other molecularly targeted drugs or in the newly diagnosed setting concurrent with chemoradiation.

SL-701 is a novel immunotherapy comprised of synthetic peptides designed to elicit an anti-tumor immune response against GBM targets: interleukin-13 receptor alpha-2, EphrinA2 and Survivin. Updated Phase 2 data are reported. Patients with previously treated GBM, bevacizumab (bev)-naive, HLA-A2+, and KPS>60, were enrolled. SL-701 with adjuvant poly-ICLC was dosed biweekly with bev (10 mg/kg) for 6 months, then q28 days. Primary endpoint was OS-12, with statistical significance determined if lower bound of 2-sided 95% Clopper Exact confidence interval (CI) is >20%. Target-specific CD8+ T-cell frequency was assessed by flow cytometry. 28 patients received median of 13 SL-701 doses with bev. Most frequent treatment-related adverse events (TRAEs) were fatigue (39%) and injection site reaction (25%). Grade 3 TRAE was fatigue (3.6%); there were no other grade 3 TRAEs. Disease control rate (complete response [CR], partial response [PR], stable disease) was 54% (n=15), with 2 CRs and 2 PRs. Median duration of disease control was 8.8 months (95% CI 3.7, NE). Median OS was 11.7 months (95% CI: 7.1, NE). The primary endpoint was met with a 50% OS-12 (95% CI: 30.6, 69.4). Target-specific CD8+ T cell activity was detected at 8–24 wks, the majority occurring by wk 16. Long-term survivors were largely comprised of patients with target-specific CD8+ T-cell responses; median OS of these immune responders was not reached. The Phase 2 trial of SL-701 + bev in previously treated GBM met its primary endpoint with a 50% OS-12. The regimen was well-tolerated and demonstrated objective responses, including CRs. There was an even more pronounced survival signal, as well as an encouraging survival tail comprised largely of target-specific CD8+ T cell responders, and the median OS of these immune responders was not reached. Updates around next steps, including leveraging potential immune-related biomarkers in a registration-directed trial design, will be provided.

2058Background: SL-701 is a novel immunotherapy comprised of synthetic peptides designed to elicit an anti-tumor immune response against GBM targets: interleukin-13 receptor alpha-2, EphrinA2 and S...

2067Background: Up to 40% of LADC patients (pts) develop BM but little is known about the inciting molecular events. Methods: We compared mutational profiles of LADC BM pts with primary (P) LADC su...

Ixabepilone is an epothilone, a novel class of non-taxane microtubule stabilizing agents. A phase I/II and pharmacokinetic trial of ixabepilone was conducted in patients with recurrent high-grade gliomas. Adult patients received ixabepilone as a 1-h infusion daily for 5 days every 3 weeks. A modified continual reassessment method was used to escalate doses, beginning at 5.0 mg/m(2), in patients stratified by use or non-use of enzyme inducing antiepileptic drugs (EIAED). In the phase I study, the maximum tolerated dose (MTD) and pharmacokinetics of ixabepilone were determined for each group. The phase II study used a two-stage design to evaluate response rate. Secondary endpoints were survival and 6-month progression free survival. In the phase I trial, 38 patients (median age 54 years) were enrolled. The MTD was 6.8 mg/m(2) for patients not taking EIAEDs and 9.6 mg/m(2) for those taking EIAEDs. The dose limiting toxicities in both groups were hematologic. Twenty-three patients (median age 54 years) were enrolled in the first stage of the phase II trial. No objective responses were observed. Median overall survival was 5.8 (95% CI, 5.0-8.6) months and 6-month PFS rate was 4% (95% CI, 0-22%). The overall mean total body clearance for ixabepilone was significantly higher (P = 0.003) in patients receiving EIAEDs (36 ± 11 l/h/m(2)) than those not (24 ± 9.2 l/h/m(2)). Patients on EIAEDs had a substantially higher MTD likely due to induction of cytochrome P450. Ixabepilone had no activity in patients with recurrent high-grade gliomas.

Bortezomib selectively binds and inhibits the 20S proteasome enzyme's active sites. This study was conducted to determine the side effects and maximum tolerated dose (MTD) of bortezomib in patients with recurrent malignant glioma. Separate dose escalations were conducted in patients taking or not taking enzyme-inducing anti-seizure drugs (+/-EIASD). The starting dose in both groups was 0.9 mg/m(2) intravenously twice weekly for the first three of each 4 week cycle. Imaging assessment of response was carried out and Plasma 20S proteasome activity inhibition and imaging was conducted to monitor efficacy. The 66 patients enrolled had a median age of 51 years, median KPS of 90%, and 77% had glioblastoma multiforme. The MTD in the -EIASD group was 1.70 mg/m(2) based on grade 3 thrombocytopenia, sensory neuropathy and fatigue. In the +EIASD group escalation was terminated at 2.5 mg/m(2) without meeting meet the MTD criteria. However, proteasome inhibition in this group did not change at doses above 1.90 mg/m(2) suggesting that further escalations would be unlikely to increase a biologic effect. Mean proteasome inhibition plateaued in +EIASD patients receiving 2.1 mg/m(2) of bortezomib at 77 ± 12% and in -EIASD patients treated with a dose of 1.7 mg/m(2) at 79 ± 6%. Two partial responses were observed. This study determined that EIASDs effect the MTD of bortezomib and the dose required for maximal inhibition of whole blood 20S proteasome. Some evidence of clinical activity was noted in this phase I study in patients with recurrent high grade gliomas.

Introduction Carmustine (BCNU)-impregnated biodegradable polymer wafers have been shown to prolong survival in patients with recurrent malignant glioma. Interferon alfa-2b (IFNα2b) has demonstrated antitumor activity against a number of cancers, but its use in glioma has been limited. The use of these agents in combination is appealing because the mode of antitumor activity likely differs. This is a report of a phase I dose-finding study for IFNα2b in combination with surgery and BCNU wafers in patients with recurrent glioblastoma. Method Patients with progressive malignant glioma that was confirmed intraoperatively to be glioblastoma were treated with surgical resection and implantation of 8 BCNU wafers. A week later, IFNα2b was initiated three times a week at a dose of 3 MU/m2, which was escalated in increments of 3 MU/m2. The treatment cycle encompassed 8 weeks. Toxicity was monitored by clinical and laboratory testing. Correlative studies of methylguanine methyltransferase (MGMT) expression and gene expression array analysis were carried out. Results Ten patients were enrolled, and 9 patients had evaluable data. Dose-limiting toxicity in the form of fatigue occurred at 9 MU/m2. Two complete imaging responses were observed at the 3 MU/m2 dose. MGMT expression and gene expression arrays did not correlate with toxicity or response. Conclusions Multimodal therapy with surgery, BCNU wafers, and IFNα2b appears to be a feasible and safe treatment strategy. The maximum tolerated dose of IFNα2b was determined to be 6 MU/m2. Analysis of MGMT expression and gene expression was feasible.

Karenitecin is a highly lipophilic camptothecin analogue with a lactone ring that is relatively resistant to inactivating hydrolysis under physiologic conditions. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of karenitecin in adults with recurrent malignant glioma (MG), to describe the effects of enzyme-inducing antiseizure drugs (EIASDs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Karenitecin was administered intravenously over 60 min daily for 5 consecutive days every 3 weeks to adults with recurrent MG who had no more than one prior chemotherapy regimen. The continual reassessment method was used to escalate doses, beginning at 1.0 mg/m(2)/day, in patients stratified by EIASD use. Treatment was continued until disease progression or treatment-related dose-limiting toxicity (DLT). Plasma pharmacokinetics was determined for the first daily dose of karenitecin. Thirty-two patients (median age, 52 years; median KPS score, 90) were accrued. Seventy-eight percent had glioblastoma, and 22% had anaplastic glioma. DLT was reversible neutropenia or thrombocytopenia. The MTD was 2.0 mg/m(2) in daggerEIASD patients and 1.5 mg/m(2) in -EIASD patients. The mean (+/-SD) total body clearance of karenitecin was 15.9 +/- 9.6 liters/h/m(2) in daggerEIASD patients and 10.2 +/- 3.5 liters/h/m(2) in -EIASD patients (p = 0.02). No objective responses were observed in 11 patients treated at or above the MTD. The total body clearance of karenitecin is significantly enhanced by the concurrent administration of EIASDs. This schedule of karenitecin, a novel lipophilic camptothecin analogue, has little activity in recurrent MG.

BACKGROUND: Cediranib is an orally available pan-VEGFR tyrosine kinase inhibitor. Previously phase III study in patients with recurrent glioblastoma did not meet primary end of progressive-free survival (PFS) (J Clin Oncol. 2013 Sep 10; 31(26): 3212-3218) METHODS: We identified 1 patient, 53-year old Caucasian female, who developed tumor progression of left posterior frontal 1.2 x 1.5 cm in February, 2009 following surgery on 10/15/08 and concurrent temozolomide (TMZ) and radiation therapy from 11/8/08 -1/6/09 with one cycle of maintenance TMZ. She was enrolled in a randomized, phase III, placebo-controlled, partially blinded clinical trial of cediranib either as monotherapy or in combination with lomustine (CCNU) versus CCNU. RESULTS: She was randomized to receive a combination therapy with 1st cycle CCNU 190 mg and cederanib 20 mg/day on 4/13/09. Four weeks later, she developed grade 4 thrombocytopenia (17, 000) associated with gum bleeding and dizziness. She received a platelet transfusion. She continued with cediranib alone and 2nd reduced CCNU 100 mg was delayed till 6/16/09, 3rd CCNU on 2/2/2010. She developed hypertension, proteinuria and diarrhea from cediranib in April of 2010 and she continued with reduced dose to 15 mg/day alone without CCNU. However, she developed nephrotic syndrome and poorly controlled hypertension and was taken off this study in May 2010. At 6-week MRI showed 50% tumor regression (PR) and complete response at 24-weeks. With no enhancement seen on MRI on 6/4/15, she has been off therapy and in clinical remission over 5 years with high functional level and good quality of life (KPS 90%). CONCLUSION: This is a case report of successful therapy for recurrent glioblastoma with long term remission despite termination of therapy > 5 years from cediranib and limited CCNU dosage.

Advances in therapy for glioblastoma (GBM) have provided limited survival and health-related quality of life (HRQoL) benefit. Symptom management and maintaining HRQoL are important metrics for assessing treatment benefit. To inform on these metrics, both clinician- and patient-reported outcome measures to evaluate HRQoL and neurocognitive impairment were included as exploratory endpoints in the randomized cohort 2 of CHECKMATE-143, evaluating nivolumab monotherapy versus bevacizumab in adult patients with recurrent GBM. Clinician assessment of neurologic function will be done using the Neurologic Assessment in Neuro-Oncology (NANO) scale, which includes nine major domains (gait, strength, ataxia, sensation, visual field, facial strength, language, level of consciousness, and behaviour). The Cogstate assessment, consisting of a computerized battery of neurocognitive tests of approximately 15 minutes in duration, was used to evaluate neurocognitive functioning, cognitive deficits and/or executive functioning at baseline, and on day 1 of weeks 13, 21, 45, and 69, and at the time of treatment discontinuation. Patient-reported HRQoL was determined using the EORTC QLQ-C30, an assessment commonly used in oncology studies and comprising six functional scales (physical functioning, cognitive functioning, emotional functioning, social functioning, role functioning, and global QoL) as well as nine symptom scales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties), and the QLQ-BN20, a brain tumor-specific instrument evaluating four domains (future uncertainty, visual disorder, communication deficit, and motor dysfunction). The standardized EuroQoL-5D will be used for self-assessment of general health status across five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety) and includes a visual analog rating scale. Scoring by using the NANO scale and assessment with the EORTC QLQ-C30, QLQ-BN20 and EQ5D will be done at baseline, weeks 7, 13, and every 8 weeks thereafter until treatment discontinuation. Methodology and baseline information regarding the use of these patient and clinician scales will be reported.

BACKGROUND: Clinical outcomes were associated with immune response of HLA-A2+ patients enrolled in a randomized phase 2 trial of ICT-107. METHODS: 124 patients (77 HLA-A2+), randomized 2:1, received ICT-107 (autologous DCs incubated with 6 synthetic peptide CTL epitopes targeting GBM tumor/stem cell-associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL-13Rα2) or matching control (un-incubated DC). Immune response was determined by a functional ELISPOT assay pre- and post-treatment (ICT-107 30.5% vs. 15.5% in controls). Determination of p-values and significance between dependent variables and overall survival (OS) or progression-free survival (PFS) was performed using log-rank test. Fisher's exact tests were performed for association between extended overall survival (EOS: OS > 22.2 months) and extended progression-free survival (EPFS: PFS > 16.5 months) and the same variables. RESULTS: HLA-A2+ patients showed evidence of immune response being associated with both OS and PFS. After determining HLA-A2 ELISPOT responders (responders) using a comprehensive scoring system, responders had a median OS of 23.1 months versus 13.7 for non-responders (p = 0.0673). Similarly, responders had an EOS percentage of 52% versus 29% non-responders (p = 0.0615). Further, responders had a significantly higher percentage of EPFS (41% versus 15%, p = 0.0259). When censored to 7.5 months post-treatment, immune response was found to significantly improve OS (median 17.6 months versus 13.7, p = 0.0018). Level of IL-12 production can be linked to survival. High IL-12 producers had a median OS of 20.6 compared to 15.4 for low producers (p = 0.0515). Within the treatment group, the difference was larger, with medians of 23.3 months versus 15.2 (p = 0.0654), and high producers had a significantly higher percentage of EOS (54% versus 31%, p = 0.0426) and EPFS (43% versus 19%, p = 0.0293). CONCLUSIONS: The associations identified between clinical outcomes of OS and PFS with immunologic response provide support for the efficacy of ICT-107 in HLA-A2+ patients due to a biologic T cell response.

Survival for glioblastoma (GBM) patients with an unmethyated MGMT promoter in their tumor is generally worse than methylated MGMT tumors, as temozolomide (TMZ) response is limited. How to better treat patients with unmethylated MGMT is unknown. We performed a trial combining erlotinib and bevacizumab in unmethylated GBM patients after completion of radiation (RT) and TMZ. GBM patients with an unmethylated MGMT promoter were trial eligible. Patient received standard RT (60 Gy) and TMZ (75 mg/m2 × 6 weeks) after surgical resection of their tumor. After completion of RT they started erlotinib 150 mg daily and bevacizumab 10 mg/kg every 2 weeks until progression. Imaging evaluations occurred every 8 weeks. The primary endpoint was overall survival. Of the 48 unmethylated patients enrolled, 46 were evaluable (29 men and 17 women); median age was 55.5 years (29-75) and median KPS was 90 (70-100). All patients completed RT with TMZ. The median number of cycles (1 cycle was 4 weeks) was 8 (2-47). Forty-one patients either progressed or died with a median progression free survival of 9.2 months. At a follow up of 33 months the median overall survival was 13.2 months. There were no unexpected toxicities and most observed toxicities were categorized as CTC grade 1 or 2. The combination of erlotinib and bevacizumab is tolerable but did not meet our primary endpoint of increasing survival. Importantly, more trials are needed to find better therapies for GBM patients with an unmethylated MGMT promoter.