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Background DNA methylation abnormalities are pervasive in pituitary neuroendocrine tumors (PitNETs). The feasibility to detect methylome alterations in circulating cell-free DNA (cfDNA) has been reported for several central nervous system (CNS) tumors but not across PitNETs. The aim of the study was to use the liquid biopsy (LB) approach to detect PitNET-specific methylation signatures to differentiate these tumors from other sellar diseases. Methods We profiled the cfDNA methylome (EPIC array) of 59 serum and 41 plasma LB specimens from patients with PitNETs and other CNS diseases (sellar tumors and other pituitary non-neoplastic diseases, lower-grade gliomas, and skull-base meningiomas) or nontumor conditions, grouped as non-PitNET. Results Our results indicated that despite quantitative and qualitative differences between serum and plasma cfDNA composition, both sources of LB showed that patients with PitNETs presented a distinct methylome landscape compared to non-PitNETs. In addition, LB methylomes captured epigenetic features reported in PitNET tissue and provided information about cell-type composition. Using LB-derived PitNETs-specific signatures as input to develop machine-learning predictive models, we generated scores that distinguished PitNETs from non-PitNETs conditions, including sellar tumor and non-neoplastic pituitary diseases, with accuracies above ~93% in independent cohort sets. Conclusions Our results underpin the potential application of methylation-based LB profiling as a noninvasive approach to identify clinically relevant epigenetic markers to diagnose and potentially impact the prognostication and management of patients with PitNETs.

Background No standard medical treatment exists for adult patients with recurrent ependymoma, and prospective clinical trials in this population have not succeeded because of its rarity and challenges in accruing patients. The Collaborative Ependymoma Research Network conducted a prospective phase II clinical trial of dose-dense temozolomide (TMZ) and lapatinib, targeting the unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status and increased expression of ErbB2 (human epidermal growth factor receptor 2) and ErbB1 (epidermal growth factor receptor) in ependymomas. Methods Patients age 18 or older with histologically proven and progressive ependymoma or anaplastic ependymoma were eligible and received dose-dense TMZ and daily lapatinib. The primary outcome measure was median progression-free survival (PFS). Landmark 6- and 12-month PFS and objective response were measured. Serial assessments of symptom burden using the MD Anderson Symptom Inventory Brain Tumor (MDASI-BT)/MDASI–Spine Tumor modules were collected. Results The 50 patients enrolled had a median age of 43.5 years, median Karnofsky performance status of 90, and a median of 2 prior relapses. Twenty patients had grade III, 16 grade II, and 8 grade I ependymoma. Half had spinal cord tumors; 15 had a supratentorial tumor, 8 infratentorial, and 2 had disseminated disease. Treatment was well tolerated. The median PFS was 7.8 months (95% CI: 5.5,12.2); the 6- and 12-month PFS rates were 55% and 38%, with 2 complete and 6 partial responses. Measures of symptom burden showed reduction in moderate-severe pain and other disease-related symptoms in most patients. Conclusions This treatment, with demonstrated clinical activity with objective responses and prolonged disease control associated with disease-related symptom improvements, is an option as a salvage regimen for adult patients with recurrent ependymoma.

Background Detection of distinct epigenetic biomarkers in circulating cell-free DNA (cfDNA) of liquid biopsy (LB) specimens (e.g. blood) fosters opportunity for prognostication of central nervous system (CNS) tumors and has not been thoroughly explored in patients with meningiomas. Material and Methods We profiled the cfDNA methylome (EPIC array) in serum specimens from patients with meningiomas (MNG; n= 63) and harnessed internal and external meningioma tissue methylome data with reported follow up (n=48). To predict recurrence risk (RR), we consolidated a tissue cohort with at least 5 years of follow up and divided them into confirmed recurrence (CR; either reported progressive disease in post-surgical imaging, or additional resections following initial surgery) and confirmed no-recurrence (CNR: no confirmed disease progression w/in at least 5-years of follow-up). Then through application of an iterative process consisting of multiple tissue- and serum-based supervised analyses, we identified risk-specific methylation markers with serum specific features which, when inputted into a random forest algorithm allowed for segregation of both tumor tissue and liquid biopsy specimens according to recurrence risk. We estimated immune cell composition using MethylCIBERSORT, where a reference methylome atlas of chosen immune cell types was utilized to deconvolute the MNG samples. Results The resulting recurrence risk classifier demonstrated an appreciable predictive power in classifying samples as high or low recurrence risk across the tumor tissue cohort (ACC: 87.5%, CUI+: 85.2%). When compared to another classifier, our model demonstrated statistically significant agreement across primary meningioma samples (κ=0.269, p=0.002), and more accurately predicted samples to recur across an expanded time window (time to recurrence >5yrs). Across resulting liquid biopsy classifications, recurrence risk subgroups were analogous with reported risk factors, including WHO grade, extent of resection, and tumor location. Recurrence risk subgroups (high and low) also demonstrated differential estimated immune cell contributions, with low-risk samples exhibiting a “hot” profile, or enrichment of B-Cells, CD56- and CD4 T-Cells, and natural killer cells. Notably, the estimated neutrophil to lymphocyte ratio, previously purported to be relevant to tumor prognosis, was appreciably higher for those meningioma samples with the highest recurrence risk. Conclusion DNA methylation markers identified in the serum are suitable for the development of machine learning-based models which present high predictive power to prognosticate patients with meningioma and estimate a differential immune profile across recurrence risk groups. After validation in an external cohort, this noninvasive approach may improve the presurgical therapeutic management of patients with meningiomas.

BACKGROUND Standard of care (SOC) and patient survival in glioblastoma have changed little in the past 17 years. We evaluated in a phase 3 trial whether adding an autologous tumor lysate-loaded dendritic cell vaccine (murcidencel) to SOC extends survival. Patients and METHODS Newly diagnosed glioblastoma patients were randomized 2:1 to either murcidencel or placebo. Under a crossover design, all patients could receive murcidencel following tumor recurrence. All parties remained blinded regarding treatments before recurrence. Patients thus received murcidencel at new diagnosis (nGBM) or at recurrence (rGBM) following crossover from placebo. The primary and secondary endpoints compare overall survival (OS) with contemporaneous, matched external controls. Four sets of analyses were conducted to ensure rigorous matching of the controls, reduce biases, and confirm the robustness of the results. RESULTS 331 patients were enrolled. With the crossover, 89% received murcidencel. Median OS (mOS) for nGBM patients (n = 232) was 19.3 months from randomization (22.4 months from surgery) with murcidencel vs. 16.5 months from randomization in the controls (HR = 0.80, p = 0.002). Survival at 48 months from randomization was 15.7% vs. 9.9%, and at 60 months was 13% vs. 5.7%. For rGBM (n = 64), mOS was 13.2 months from relapse vs. 7.8 months in the controls (HR = 0.58, p < 0.001). Survival at 24 months post-recurrence was 20.7% vs. 9.6%, and at 30 months post-recurrence was 11.1% vs 5.1%. In nGBM patients with methylated MGMT (n = 90), mOS was 30.2 months from randomization (33 months from surgery) with murcidencel vs. 21.3 months from randomization in the controls (HR = 0.74, p = 0.027). The treatment was well tolerated, with only 5 serious adverse events deemed at least possibly related to the vaccine. CONCLUSION Clinically meaningful and statistically significant survival extension was seen in both nGBM and rGBM patients treated with murcidencel and SOC compared with contemporaneous, matched external controls who received SOC alone.

Background GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a biomarker based, multi-arm, international, seamless Phase 2/3 Response Adaptive Randomization platform trial designed to rapidly identify experimental therapies that improve overall survival and confirm efficacious experimental therapies and associated biomarker signatures to support new drug approvals and registration. It is a collaboration between academic investigators, patient organizations and industry, under the sponsorship of the non-profit organization, Global Coalition for Adaptive Research, to support new drug applications for newly diagnosed and recurrent GBM. Material and Methods The primary objective of GBM AGILE is to identify therapies that effectively improve overall survival in patients with newly diagnosed or recurrent GBM. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. Operating under a master protocol, GBM AGILE allows multiple drugs from different pharmaceutical companies to be evaluated simultaneously and/or over time against a common control arm. Based on performance, a drug may graduate and move to a Stage 2 (Phase 3) within the trial, and the totality of the data can be used for a new drug application and registration process. New experimental therapies are added as information about promising new drugs is identified while other therapies are removed as they complete their evaluation. The master protocol/ trial infrastructure includes efficiencies through an adaptive trial design, shared control arm and operational processes such as risk-based monitoring and enhanced remote activities. With its adaptable structure, GBM AGILE has continued trial activation, inclusion of new investigational therapies, and enrollment globally through the challenges of a global pandemic.GBM AGILE provides an efficient mechanism to screen and develop robust information regarding the efficacy of proposed novel therapeutics and associated biomarkers for GBM and to quickly move therapies and biomarkers into clinic. GBM AGILE received initial approval from the United States FDA in April 2019, and in Europe through the Voluntary Harmonization Procedure (VHP) in April, 2021. As of 2022, AGILE has screened over 1000 patients studying multiple investigational treatments. Enrollment rates are 3 to 4 times greater than traditional GBM trials, with active sites averaging 0.75 to 1 patients/site/month. Currently, there are 41 sites activated in the US, 4 in Canada and 2 in Switzerland and an estimated 24 sites yet to open in Germany, France, Switzerland, Italy and Austria. In addition to the continued expansion in Europe, effort is undergoing to extend the trial to China and Australia as well. Clinical trial information: NCT03970447

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

Author(s): Cloughesy, Timothy F; Landolfi, Joseph; Vogelbaum, Michael A; Ostertag, Derek; Elder, James B; Bloomfield, Stephen; Carter, Bob; Chen, Clark C; Kalkanis, Steven N; Kesari, Santosh; Lai, Albert; Lee, Ian Y; Liau, Linda M; Mikkelsen, Tom; Nghiemphu, Phioanh; Piccioni, David; Accomando, William; Diago, Oscar R; Hogan, Daniel J; Gammon, Dawn; Kasahara, Noriyuki; Kheoh, Thian; Jolly, Douglas J; Gruber, Harry E; Das, Asha; Walbert, Tobias | Abstract: Background:Vocimagene amiretrorepvec (Toca 511) is an investigational gamma-retroviral replicating vector encoding cytosine deaminase that, when used in combination with extended-release 5-fluorocytosine (Toca FC), results preclinically in local production of 5-fluorouracil, depletion of immune-suppressive myeloid cells, and subsequent induction of antitumor immunity. Recurrent high-grade glioma (rHGG) patients have a high unmet need for effective therapies that produce durable responses lasting more than 6 months. In this setting, relapse is nearly universal and most responses are transient. Methods:In this Toca 511 ascending-dose phase I trial (NCT01470794), HGG patients who recurred after standard of care underwent surgical resection and received Toca 511 injected into the resection cavity wall, followed by orally administered cycles of Toca FC. Results:Among 56 patients, durable complete responses were observed. A subgroup was identified based on Toca 511 dose and entry requirements for the follow-up phase III study. In this subgroup, which included both isocitrate dehydrogenase 1 (IDH1) mutant and wild-type tumors, the durable response rate is 21.7%. Median duration of follow-up for responders is 35.7+ months. As of August 25, 2017, all responders remain in response and are alive 33.9+ to 52.2+ months after Toca 511 administration, suggesting a positive association of durable response with overall survival. Conclusions:Multiyear durable responses have been observed in rHGG patients treated with Toca 511 + Toca FC in a phase I trial, and the treatment will be further evaluated in a randomized phase III trial. Among IDH1 mutant patients treated at first recurrence, there may be an enrichment of complete responders.

INTRODUCTION High grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication (HGNET BCOR) is a recently described tumor entity of the central nervous system (CNS) with a distinct methylation profile and characteristic genetic alteration. We report the outcome of two cases after 1st line multimodality therapy. MATERIAL AND METHOD A 7 year old girl with a ventricular tumour and a 6 year old boy with a tumour in the occipital region with infiltration of the transverse and sigmoid sinus were both diagnosed based on histology and methylation with HGNET-BCOR. No spinal or liquor dissemination were found at diagnosis in both cases. Treatment consisted of radical resection of the tumour. In the case of the lesion with sinus infiltration residual tumour in the vessel could not be removed. Both children were postoperatively treated with radiotherapy (craniospinal 36 Gy and boost to 54 Gy), concomitant Vincristin and adjuvant Cisplatin, Lomustine and Vincristine. RESULTS The girl developed a local recurrence at the primary tumour site 18 months after diagnosis. Reoperation showed the same histology. Start of 2nd line chemotherapy with Temozolomid and Irinotecan is being discussed. The boy with sinus infiltration developed seven months after diagnosis multiple liver, lung and bone metastasis. Biopsy of a liver lesion showed HGNET-BCOR. He was treated with Temozolomid, Irinotecan and died nine months after diagnosis. CONCLUSION We report two cases with failure after 1st line treatment for HGNET-BCOR. To our knowledge HGNET-BCOR with development of hematological disease dissemination is a rare finding.

INTRODUCTION Intracranial malignant germ cell tumours (iGCT) are rare brain tumours mainly diagnosed in children and younger adults. MATERIAL AND METHODS A retrospective analysis was performed by chart review of patients treated for iGCT in the northern and central region of Denmark. Teratoma only patients were not included in the study. RESULTS 20 patients with iGCT were diagnosed from 2008–2019 in Western Denmark. The cumulative incidence was 1.05 per 100.000. The yearly incidence was 0.1 per 100.000. Mean age at diagnosis was 18 years (range 8–36 years), 17 were males and 3 were females. 13 patients presented with germinoma and 7 patients with non germinomateous germ cell tumours (NGGCT). Three patients had disseminated disease, two with germinoma and one with NGGCT. All patients had received radiotherapy and 18 patients were treated with multidrug chemotherapy including platinum and etoposide before irradiation. Two patients experienced recurrent disease, both non disseminated at diagnosis, one patient with germinoma and one patient with NGGCT. Both received salvage treatment including high dose chemotherapy with stem cell transplantation and reirradiation. Two NGGCT patients died, one patient after development of an anaplastic astrocytoma in the radiation field five years after radiotherapy and one patient after intracranial hemorraghe 18 months after salvage treatment for recurrent disease. Overall survival was 90%, 100% for GCT and 71% for NGGCT. CONCLUSION The outcome of patients with iGCT in Western Denmark was comparable to the literature. A nationwide study of epidemiology and outcome of iGCT in Denmark is planned.

Author(s): Ellingson, Benjamin M; Aftab, Dana T; Schwab, Gisela M; Hessel, Colin; Harris, Robert J; Woodworth, Davis C; Leu, Kevin; Chakhoyan, Ararat; Raymond, Catalina; Drappatz, Jan; de Groot, John; Prados, Michael D; Reardon, David A; Schiff, David; Chamberlain, Marc; Mikkelsen, Tom; Desjardins, Annick; Holland, Jaymes; Ping, Jerry; Weitzman, Ron; Wen, Patrick Y; Cloughesy, Timothy F | Abstract: Background:To overcome challenges with traditional response assessment in anti-angiogenic agents, the current study uses T1 subtraction maps to quantify volumetric radiographic response in monotherapy with cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (MET), and AXL, in an open-label, phase II trial in patients with recurrent glioblastoma (GBM) (NCT00704288). Methods:A total of 108 patients with adequate imaging data and confirmed recurrent GBM were included in this retrospective study from a phase II multicenter trial of cabozantinib monotherapy (XL184-201) at either 100 mg (N = 87) or 140 mg (N = 21) per day. Contrast enhanced T1-weighted digital subtraction maps were used to define volume of contrast-enhancing tumor at baseline and subsequent follow-up time points. Volumetric radiographic response (g65% reduction in contrast-enhancing tumor volume from pretreatment baseline tumor volume sustained for more than 4 wk) was tested as an independent predictor of overall survival (OS). Results:Volumetric response rate for all therapeutic doses was 38.9% (41.4% and 28.6% for 100 mg and 140 mg doses, respectively). A log-linear association between baseline tumor volume and OS (P = 0.0006) and a linear correlation between initial change in tumor volume and OS (P = 0.0256) were observed. A significant difference in OS was observed between responders (median OS = 20.6 mo) and nonresponders (median OS = 8.0 mo) (hazard ratio [HR] = 0.3050, P l 0.0001). Multivariable analyses showed that continuous measures of baseline tumor volume (HR = 1.0233, P l 0.0001) and volumetric response (HR = 0.2240, P l 0.0001) were independent predictors of OS. Conclusions:T1 subtraction maps provide value in determining response in recurrent GBM treated with cabozantinib and correlated with survival benefit.

BACKGROUND Somatic oncogene amplification happens frequently in glioblastoma (GBM). The second most frequently amplified gene encoding receptor tyrosine kinases in GBMs is platelet derived growth factor alpha (PDGFRA) (15%). In contrast, MYC and MYCN amplification occurs in 1.6% and 2.9%, respectively. Our goal was to characterize the role of PDGFRɑ and Myc in GBM. MATERIAL AND METHODS Neurosphere cultures were implanted in cohorts of 10–15 nude mice. 5 PDX lines, presenting median survival of 29–59 days were classified as short survivors, and 5 lines with median survival between 104–134 days classified as long survivors. Total RNA was extracted from PDX terminal tumors (3 biological replicates) and sequenced in a paired-end read format. Mouse reads were filtered out using Xenome. MYC and PDGFRA expression patterns were analyzed in tissue microarrays representing duplicated samples from 40 glioma neurosphere-derived PDX lines by IHC (1 anaplastic oligodendroglioma, 8 recurrent GBM with 2 newly diagnosed/recurrent pairs). Normalized staining intensity (MI) and area (A) were quantified using Fiji/ImageJ. RESULTS PDGFRA, MYC, MYCN gene amplifications were represented in a molecularly diverse panel of GBM patient-derived cancer stem-like cells (CSC) and orthotopic mouse xenografts (PDX). Transforming to a normal distribution (log10), 4/13 of cell lines had a PDGFRA mRNA expression (RPKM) higher than 1.5. Similarly, one PDX line had a staining index of greater than 10, 11 (27.5%) had an index between 5–10. The range of intra-tumoral variance, represented by standard deviation, was 0.09–24.25 highlighting the heterogeneity of PDGFRɑ expression. PDGFRɑ phosphorylation (Y754) did not differ between 8 cell lines cultured in NMGF, but deviated in alternate medias without growth factors, supplemented with FBS. In comparison, MYC(N) mRNA expression is only elevated in the context of a known amplification. Furthermore, a a MYC activity signature consisting of 18 target genes was only evident in the 5 amplified CSC lines. Taking advantage of genomic heterogeneity, we have isolated subclones lacking PDGFRA amplification from a PDGFRA amplified GBM CSC. The absence of PDGFRA amplification reduced the self-renewal potential to 37% of the PDGFRA amplified cell population (p=0.001) in clone 1 and 57% in clone 2 (p=0.013). Pertaining to determinants of in vivo survival, MYC was altered in 80% of short survivors (2/5 MYC, 2/5 MYCN amplification) and in 0% of long survivors. Myc signature was highly correlated with in vivo survival (Pearsons’ corr. = -0.77) and MYC gene expression was correlated with in vivo TMZ resistance (corr. = 0.7). CONCLUSION These results suggest that PDGFRɑ expression and activity can occur in the absence of gene amplification, while Myc activity is dependent on gene amplification. Both oncogenes drive oncogenic pathways that should be explored as therapeutic targets.

BACKGROUND: Survival outcomes for patients with glioblastoma remain poor, particularly for patients with unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter. This phase II, randomized, open-label, multicenter trial investigated the efficacy and safety of 2 dose regimens of the selective integrin inhibitor cilengitide combined with standard chemoradiotherapy in patients with newly diagnosed glioblastoma and an unmethylated MGMT promoter. METHODS: Overall, 265 patients were randomized (1:1:1) to standard cilengitide (2000 mg 2×/wk; n = 88), intensive cilengitide (2000 mg 5×/wk during wk 1-6, thereafter 2×/wk; n = 88), or a control arm (chemoradiotherapy alone; n = 89). Cilengitide was administered intravenously in combination with daily temozolomide (TMZ) and concomitant radiotherapy (RT; wk 1-6), followed by TMZ maintenance therapy (TMZ/RT→TMZ). The primary endpoint was overall survival; secondary endpoints included progression-free survival, pharmacokinetics, and safety and tolerability. RESULTS: Median overall survival was 16.3 months in the standard cilengitide arm (hazard ratio [HR], 0.686; 95% CI: 0.484, 0.972; P = .032) and 14.5 months in the intensive cilengitide arm (HR, 0.858; 95% CI: 0.612, 1.204; P = .3771) versus 13.4 months in the control arm. Median progression-free survival assessed per independent review committee was 5.6 months (HR, 0.822; 95% CI: 0.595, 1.134) and 5.9 months (HR, 0.794; 95% CI: 0.575, 1.096) in the standard and intensive cilengitide arms, respectively, versus 4.1 months in the control arm. Cilengitide was well tolerated. CONCLUSIONS: Standard and intensive cilengitide dose regimens were well tolerated in combination with TMZ/RT→TMZ. Inconsistent overall survival and progression-free survival outcomes and a limited sample size did not allow firm conclusions regarding clinical efficacy in this exploratory phase II study.

Author(s): Wen, Patrick Y; Drappatz, Jan; de Groot, John; Prados, Michael D; Reardon, David A; Schiff, David; Chamberlain, Marc; Mikkelsen, Tom; Desjardins, Annick; Holland, Jaymes; Ping, Jerry; Weitzman, Ron; Cloughesy, Timothy F | Abstract: BackgroundCabozantinib is a tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET that has demonstrated clinical activity in advanced solid tumors. This open-label, phase II trial evaluated cabozantinib in patients with recurrent or refractory glioblastoma (GBM).MethodsPatients were initially enrolled at a starting dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of toxicity. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, and safety.ResultsAmong 152 patients naive to prior antiangiogenic therapy, the objective response rate was 17.6% and 14.5% in the 140 mg/day and 100 mg/day groups, respectively, which did not meet the predefined statistical target for success. The proportions of patients alive and progression free at 6 months were 22.3% and 27.8%, respectively. Median progression-free survival was 3.7 months in both groups, and median overall survival was 7.7 months and 10.4 months, respectively. The incidence of grade 3/4 adverse events (AEs) was 79.4% and 84.7% in the 140 mg/day and 100 mg/day groups, respectively, and dose reductions due to AEs were experienced by 61.8% and 72.0%, respectively. Common grade 3/4 AEs included fatigue, diarrhea, and palmar-plantar erythrodysesthesia syndrome.ConclusionsCabozantinib showed evidence of clinical activity in patients with recurrent GBM naive to antiangiogenic therapy, although the predefined statistical target for success was not met. At the starting doses assessed, AEs were frequently managed with dose reductions.Clinical trials registration numberNCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288).

Glioblastoma is the most common primary brain malignancy and is associated with poor prognosis despite aggressive local and systemic therapy, which is related to a paucity of viable treatment options in both the newly diagnosed and recurrent settings. Even so, the rapidly increasing number of targeted therapies being evaluated in oncology clinical trials offers hope for the future. Given the broad range of possibilities for future trials, the Brain Malignancy Steering Committee convened a clinical trials planning meeting that was held at the Udvar-Hazy Center in Chantilly, Virginia, on September 19 and 20, 2013. This manuscript reports the deliberations leading up to the event from the Targeted Therapies Working Group and the results of the meeting.

BACKGROUND: Human glioblastomas (GBMs) are highly angiogenic tumors characterized by a rapid tumor growth. In radiological studies, the preoperative speed of growth of treatment-naïve human GBMs varies considerably among patients. Faster GBM growth has been related to increased angiogenesis and hypoxia in animal models; however, such links have been sparsely studied in human patients. We have therefore aimed to look for associations between microvessel density (MVD) counts by means of two endothelial markers and radiological speed of growth. MATERIAL AND METHODS: In 102 patients with newly diagnosed GBMs, MVDs were counted using immunohistochemical staining of von Willebrand factor (vWF, factor VIII), a pan-endothelial marker, and CD105 (endoglin), a marker of proliferating endothelial cells. Radiological speed of growth was estimated from preoperative tumor volumes on two contrast-enhanced T1-weighted MRI scans taken ≥14 days apart. Because speed of growth has previously been shown to be highly associated with initial tumor volume, an expected Gompertzian growth curve fitted from the volume data and the interval between the scans was used to dichotomize the patients into two groups; tumors with a larger or smaller volume increase than expected from the curve (i. e. faster or slower growing tumors, respectively). These groups were assessed for associations with the MVDs using Mann-Whitney U tests and a multivariable binary logistic regression analysis, which included histopathological features previously found to independently predict faster GBM growth. RESULTS: CD105-MVD was the only marker significantly associated with faster growth in a univariable analysis (P = 0.049). However, when corrected for the presence of thromboses and high cellular density in a multivariable model, CD105-MVD was no longer significant. In this model, thromboses and high cellular density were significant independent predictors of faster growth with OR 4.2 (95% CI 1.2–14.3, P = 0.021) and OR 2.6 (95% CI 1.0–6.5, P = 0.048), respectively. CONCLUSION: Our results show that vWF-MVD and CD105-MVD are not independently associated with faster GBM growth, suggesting faster GBM growth is also driven by angiogenesis-independent processes.

BACKGROUND: Genome-wide DNA methylation profiling has shown that epigenetic abnormalities are biologically important in glioma and can be used to classify these tumors into distinct prognostic groups. Thus far, DNA profiling has required surgically resected glioma tissue; however, gliomas release tumoral material into biofluids providing an opportunity for a minimally invasive testing. While prior studies have shown that molecular markers can be detected in liquid biopsy (LB), there has been low sensitivity for tumor-specific markers. We hypothesize that the low sensitivity is due to the targeted assay methods. METHODS: Genome-wide CpG methylation levels in DNA of tumor tissue and cell-free DNA serum of glioma patients. RESULTS: We defined glioma-specific and IDH-specific epigenetic LB (eLB) signatures (Glioma-eLB and IDH-eLB, respectively) from serum cell-free DNA from patients diagnosed with glioma (N=15 IDH mutant and N=7 IDH wildtype) and with epilepsy (N=3). The epigenetic profiles of the matched tissue demonstrate that these eLB signatures reflected the signature of the tumor. Through cross-validation we show that Glioma-eLB can accurately predict a patient’s glioma from those with other neoplasias (N=6 Colon; N=14 Pituitary; N=3 Breast; N=4 Lung), non-neoplastic immunological conditions (N=22 sepsis; N=9 pancreatic islet transplantation), and from healthy individuals (sensitivity: 98%; specificity: 99%). Finally, IDH-eLB includes promoter methylated markers associated with genes known to be involved in glioma tumorigenesis (PVT1 and CXCR6). CONCLUSIONS: The application of the non-invasive eLB signature discovered in this study has the potential to complement the standard of care for patients harboring glioma. This project is supported by the Henry Ford Health System, Department of Neurosurgery and the Hermelin Brain Tumor Center Foundation (A30935), United States National Institutes of Health (R01CA222146), and United States Department of Defense (CA170278)