bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal analysis of quality of life following treatment with asunercept plus reirradiation versus reirradiation in progressive glioblastoma patients.
Authors: Wick Wolfgang , Krendyukov Andriy , Junge Klaus , Höger Thomas , Kunz Claudia , Fricke Harald 
Published: May 2019

2022 Background: Palliation of symptoms and the maintenance of quality of life (QoL) are important goals in cancer treatment.1,2 Beyond progression free survival (PFS) and overall survival (OS), health related QoL was one of the secondary endpoints in the asunercept plus irradiation Phase II trial (NCT01071837) in recurrent glioblastoma.3 Current analysis presents time to deterioration (TtD) of QoL using data from this study. Methods: Data from patients (pts) with a baseline and ≥1 post-baseline QoL assessment were included in this analysis. TtD was defined as the time from randomization to the first deterioration in the EORTC QLQ-C15, PAL EORTC QLQ-BN20 and Medical Research Council (MRC)-Neurological status. Deterioration was defined as a decrease of ≥10 points from baseline in the QLQ-C15 PAL overall QoL and functioning scales, an increase of ≥10 points from baseline in the QLQ-C15 PAL fatigue scale and the QLQ-BN20 total sum of score, and a rating of “Worse” in the MRC-Neurological status. Pts without a deterioration were censored at the last QoL assessment. Kaplan-Meier estimates were used to describe TtD and both treatment groups compared using the logrank test. The relationship between progression of disease (PD) and QoL deterioration has been investigated. Results: Compared to reirradiation alone, treatment with asunercept + reirradiation was associated with significant improvement of TtD (P≤0.01; Table). PD was a key driver for QoL deterioration and the median TtD was comparable with PFS in favour of the asunercept treatment arm. Conclusions: Treatment with asunercept plus irradiation significantly prolongs TtD and maintains QoL, versus reirradiation alone in progressive glioblastoma patients. Clinical trial information: NCT01071837. References: 1. NCCN. Central Nervous System Cancers. Version 2018.2; 2. Stupp R et al. Ann Oncol 2014;25(S3):iii93-iii101; 3. Wick et al. Clin Cancer Res 2014;20:6304–13.[Table: see text]
Study of tumor infiltrating immune CELLS and vasculature in human gliomas: Differences in IDH1/2 mutant versus IDH1/2WT tumors.
Authors: Martin Soberón Maria Cruz , Sepulveda Sanchez Juan Manuel Manuel , Gargini Ricardo , Segura Berta , Gutierrez Jacquelin , Ruano Yolanda , Cantero Diana , Hernandez-Lain Aurelio , Sanchez-Gomez Pilar , Perez-Núñez Angel , Jimenez Roldan Luis , Marín Patricia , Castellano Daniel E. , De Velasco Guillermo , Cejalvo Teresa 
Published: May 2019

2030 Background: Gliomas harboring mutations in IDH1/2 show a higher overall survival time than “wild type” (wt) tumors. Although the clinical aspects are well described, little is known about the underlying mechanisms by which these mutations generate such a difference in the clinical course. Our group has recently described that IDH1/2 mutations induce a distinct vascular phenotype in the tumors, with less blood-brain barrier (BBB) leakage than the IDH1/2 wt gliomas (In Press, DOI:10.1101/541326). Methods: Prospective study analyzing a cohort of 20 patients with primary gliomas resected in one institution. Samples were obtained in the first surgery and 12 IDHmut and 8 IDHwt gliomas were included. Immune infiltration was analysed by flow cytometry and vasculature by inmunohistochemistry. For molecular biology studies, western blots were performed with Mini-PROTEAN system. Proteins were visible by enhanced chemoluminescence. Results: We show that the immune component also differentiates these two pathologies. There is significantly less immune infiltration in IDH1/2 mutant gliomas. Within the CD45 subset, IDH1/2 mutant gliomas have a reduced proportion of T lymphocytes with a different T cell exhaustion profile and an increased proportion of CD11b+ cells in comparison to IDH1/2 wt cases. Myeloid compartment distribution is also different in these two types of tumors, showing an augmented proportion of the M2 (CD206+) and the neutrophil subsets in IDH1/2 wt gliomas. Moreover, a higher proportion of CD45 PDL1+ was present in the IDH1/2 wt tumors samples. The analysis of the vasculature showed an increase density and the lumen size of the vessels of the IDH1/2 wt compared to the IDH1/2 mutant gliomas which correlate with changes in the immune profile. The biochemical analysis showed that there is an increment in EGFR and PDGFR activity in the IDH wt gliomas that is related with more vascular aberrations and higher CD45 infiltrate. This suggests that EGFR and PDGFR are the key regulators of the tumor microenvironment. Conclusions: To understand the matching between the immune infiltration and vasculogenesis is relevant for interpreting data coming from the clinical trials with checkpoints inhibitors. At the time abstract submission survival analysis is not yet available due to the short time of follow-up but in May 2019, the number of expected events for analysis will be reached.
MDNA55: A locally administered IL4 guided toxin as a targeted treatment for recurrent glioblastoma.
Authors: Randazzo Dina , Achrol Achal , Aghi Manish K. , Bexon Martin , Brem Steven , Brenner Andrew Jacob , Butowski Nicholas A. , Chandhasin Chandtip , Chowdhary Sajeel A. , Coello Melissa , Floyd John , Kesari Santosh , Merchant Fahar , Merchant Nina , Vogelbaum Michael A. , Vrionis Frank D , Zabek Miroslaw , Sampson John H. 
Published: May 2019

2039 Background: IL4 receptor (IL4R) is frequently and intensely expressed on a variety of human cancers and is associated with poor survival outcomes. Determining the role of the IL4R biomarker in glioblastoma (GBM) will be important for treatment with targeted therapies such as the IL4 fusion toxin MDNA55. Methods: A classification for IL4Rα expression in GBM tissues by H-Score was developed using a validated immunohistochemistry-based approach. MDNA55-05 is an open-label study of MDNA55 administered intratumorally via convection enhanced delivery in recurrent GBM. Levels of IL4Rα expression were assessed retrospectively in 24 subjects in the clinical trial and were correlated with GBM history, imaging responses and survival outcomes following treatment with MDNA55 to explore clinical validation. Results: Range, linearity, specificity and sensitivity testing using a rabbit polyclonal antibody to IL4Rα were performed using normal cortex (negative control) and a panel of normal human tissues and GBM cases from tissue banks. A total of 41 GBM samples were screened and grouped by reactivity thresholds: H-Scores ≥50 were observed in 95% of cases (39/41), H-Scores ≥200 were observed in 51% of cases (21/41), and H-Scores ≥250 were observed in 24% of cases (10/41). GBM tissues obtained at initial diagnosis from subjects enrolled in the trial show that moderate/high IL4R expression (H-Score > 75) was associated with shorter time to first relapse when compared to subjects with low IL4R expression (H-Score ≤ 75) (10.3 mos vs. 16.7 mos, respectively) after upfront standard-of-care treatment, consistent with published findings that IL4R expression is associated with more aggressive disease. Remarkable decreases in tumor size seen in some subjects following MDNA55 treatment were associated only with moderate/high IL4R expression and survival rate at 12 months in this group was also improved (OS12 = 55%) compared to subjects with low IL4R expression (OS12 = 30%). Conclusions: Treatment options for patients with recurrent GBM are very limited and positive outcomes remain rare. Targeting therapies such as MDNA55 by IL4R status may improve patient outcomes and help guide patient selection strategies for future clinical studies. Clinical trial information: NCT02858895.
Interim results of a phase I/IIa trial of a therapeutic CMV vaccine against recurrent glioblastoma (GBM).
Authors: Lassman Andrew B. , Reardon David A. , Lee Eudocia Quant , Iwamoto Fabio Massaiti , Diaz-Mitoma Francisco , Anderson David E , Wen Patrick Y. 
Published: May 2019

2048 Background: Cytomegalovirus (CMV) antigens have been reported in over 90% of GBM tumors. CD4+and CD8+T cells are most frequently directed against the gB and pp65 antigens, respectively, and are immunogenic targets in a CMV-based GBM vaccine. Methods: We have initiated a phase I/IIa clinical trial for patients with recurrent GBM using gB/pp65 enveloped virus-like particles (eVLPs) formulated with GM-CSF and administered intradermally. Subjects are vaccinated monthly until tumor progression, with immunomonitoring performed 2 weeks after each vaccination and MRI exams every 6 weeks. In phase I, eligible patients were age 18-70 with Karnofsky Performance Status at least 70, normal end-organ function, on stable or decreasing corticosteroids of at most 4mg dexamethasone (or equivalent), with recurrent GBM following any standard initial therapy and any number of recurrences. The primary endpoint was safety/tolerability and secondarily to assess immunogenicity. Three vaccine doses (0.4µg, 2µg, and 10µg pp65) were evaluated with 6 subjects in each cohort and DSMB safety review of the first 3 subjects in each cohort prior to enrolling additional subjects. Results: The DSMB identified no DLTs or safety concerns with any of the doses. Grade 2, 3 or 4 AEs occurred in 66%, 22% and 11% of participants, respectively, but were not related to vaccine administration. Twelve men and 6 women were enrolled with a median age 54 (range 39-66). Prior therapies included radiotherapy, temozolomide, and nivolumab. Immunological analyses demonstrate robust boosting of CMV-specific antibody titers and T cell responses against both gB and pp65 antigens in some but not all subjects, across all dose cohorts. Boosting of IFN-gsecreting T cells (measured by ELISPOT) exceeded the assay threshold for several subjects. Stable disease by MRI of 3 months or greater has been observed in 2 subjects in the high dose cohort and 1 subject in the low dose cohort and may correlate with vaccine response. Conclusions: The phase IIa extension phase of the trial planned to begin in Q2 2019 is designed to explore efficacy in an additional 10 subjects that will receive the optimal vaccine dose and includes the additional requirements of unifocal, measurable enhancing tumor 1-3 cm across at first recurrence and no prior immunotherapy. Clinical trial information: NCT03382977.
Evaluation of controlled IL-12 as monotherapy in subjects with recurrent GBM.
Authors: Lukas Rimas Vincas , Chiocca E. Antonio , Kurz Sylvia Christine , Yu John , Landolfi Joseph C. , Rao Ganesh , Barrett John A. , Buck Jill Y. , Demars Nathan , Smith Amy , Miao John , Zhou Qiang (John) , Gelb Arnold Bruce , Cooper Laurence 
Published: May 2019

2053 Background: Interleukin-12 (IL-12), a master regulator of the immune system, results in anti-tumor responses in preclinical models, but safe use requires tightly controlled production. It was conditionally produced in Ph1 “main” study (NCT02026271) in subjects with recurrent glioblastoma (rGBM) using a replication-incompetent adenovirus modified to express IL-12 under transcriptional control of the proprietary RheoSwitch Therapeutic System (Ad-RTS-hIL-12, Ad) regulated by dose of veledimex (V). Monotherapy resulted in sustained intra-tumor influx of activated cytotoxic T cells, consistent with immune-mediated anti-tumor effect, improving overall survival (OS). This correlated with increased circulating CD8+/FoxP3+ T-cell ratio (“cytoindex”), an emerging biomarker of OS. While widely used with neurosurgery, dexamethasone (dex) blunts response to immunotherapies, nevertheless median mOS of subjects who received 20mg V of 12.7 mo (n=15) at 13.1 mo follow-up. However, subanalysis (n=6) showed low-dose dex (total ≤20 mg) during V dosing improved mOS (17.8 mo). We report a 36 subject substudy in rGBM with limited dex, total rGBM treated (n=70+). Methods: Ongoing Phase 1 substudy (NCT03679754) assesses safety and tolerability of local, inducible IL-12 by single intratumoral injection of Ad (2 x 1011 viral particles) + V (20 mg PO QD x15 doses Days 0-14) in subjects not receiving dex 4 wks prior to Ad. Results: As of 03Jan19, the majority of new subjects received low-dose dex (total ≤20mg Days 0-14). The initial impact of dex on mOS will be reported. As in the main study, Ad+V 20 mg respectively increased (median) serum IL-12 and downstream IFN-g from Days 0-3: 0.8 to 8.8 pg/mL and 0 to 8.6 pg/mL. Between Days 0-14, there was net increase in cytoindex (from 20 to 46). The safety profile was similar to the main study with the main adverse reaction (AR) being mild to moderate cytokine release syndrome (CRS) characterized by flu-like symptoms. No grade 4 CRS was noted; all ARs were manageable and reversable upon holding V. Conclusions: Local, controlled IL-12 production using the Ad + V platform in subjects with rGBM safely activates the immune system and when dex is limited, appears to further improve mOS, which warrants continued investigation. Clinical trial information: NCT03679754.
Analysis of the EF-14 phase III trial reveals that tumor treating fields alter progression patterns in glioblastoma.
Authors: Jeyapalan Suriya A. , Toms Steven A , Hottinger Andreas Felix , Kleinberg Lawrence , Pollom Erqi , Soltys Scott G. , Glas Martin 
Published: May 2019

2055 Background: The EF-14 [NCT00916409] trial showed that addition of alternating electric fields (Tumor Treating Fields, TTFields) to Temozolomide (TMZ) resulted in improved survival in newly diagnosed Glioblastoma (GBM) patients with supratentorial tumors treated compared to TMZ alone. TTFields delivery is planned to optimize dose at the tumor bed, leading to the hypothesis that TTFields treated patients are more likely to exhibit distal progressions, including progression to the infratentorial brain where TTFields dose is minimal when targeting the supratentorium. Here we present analysis of the EF-14 trial testing this hypothesis. Methods: Patients on treatment for more than two months who had an MRI that exhibited progression were included in the study (treatment: N=280/466, control: N=122/229). Regions of enhancing tumor, necrosis and resection were contoured on T1 contrast MRIs acquired at baseline and at the date of first progression. New lesions at progression were classified as distal if they appeared outside of a Proximal Boundary Zone (PBZ) of 20 mm surrounding the lesions identified in the baseline MRI. The rate of occurrence of distal progressions in the TTFields-treated arm was compared to the rate observed in the control arm. Patients with (distal) infratentorial progression were identified. Results: Distal progressions were more common in the treatment arm (49/280 (18%) vs. 10/122 (8%) P<0.02; chi-squared). Infratentorial progression were observed in 4% (10 patients) of the treatment arm vs. 0 patients in the control (P<0.002 t-test). Distal lesions at progression were more distant from the original lesion in the TTFields treated arm (58.57 + 28.12 mm vs 46.61 + 20.48 mm, P<0.02; Wilcoxon rank sum test. The relative tumor growth rates in TTFields treated patients were significantly slower than those observed in the control arm (0.036+ 0.126 ml/day vs. 0.036+ 0.183 ml/day P<0.03; t-test). Conclusions: This analysis indicates that adding TTFields to TMZ could impact GBM growth patterns. The results suggest that TTFields increases local control of tumor growth, emphasizing the need for adaptive treatment after progression to control progressing disease. Clinical trial information: NCT00916409.
Detection of targetable somatic alterations in glioblastoma (GBM) and clinical impact.
Authors: Fusco Michael , Macaulay Robert J , Forsyth Peter A. J. , Walko Christine Marie 
Published: May 2019

2058 Background: In GBM, molecular markers are utilized to establish an integrated diagnosis as described in the WHO 2016 guidelines and identify patients (pts) with molecular targets amenable to therapeutic intervention. Herein we review our experience at Moffitt Cancer Center. Methods: A retrospective chart review between 4/1/2013 and 11/1/2018 was performed to collect demographic, clinical, disease, treatment and outcome variables on 163 unique pts with GBM whose tumors underwent comprehensive genomic profiling by FoundationOne or CDx testing. Genomic data was analyzed for recurrent alterations and tumor mutational burden (TMB). Results: Median age was 58 years (range 19 to 85). 13% were IDH1 or 2-mutated. Among the 141 IDH-wild type (wt) pts, TERT promoter mutations occurred in 83% and CDKN2A/B co-deletion in 65%. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was seen in 33%. A median of 5 clinically relevant alterations were identified per tumor sample (range, 2 to 34) and a median of 2 mutations (range, 0 to 6) were found to be actionable after review by our molecular tumor board. The most commonly actionable alterations were found in EGFR, BRAF and genes associated with homologous recombination deficiency (HRD) (see table). Four pts were treated with EGFR-targeted therapy, one pt with an HRD alteration received a PARP inhibitor (progression free survival [PFS] of 34 weeks), and two pts with BRAF V600E received dabrafenib/trametinib combination therapy (treatment ongoing at 14 weeks and 38 months, respectively). Median TMB (n = 118) was 4 (range, 0 to 371 Muts/Mb). One pt who received 44 months of temozolomide exposure had a hypermutated tumor (371 Muts/Mb) and was treated on trial with pembrolizumab, but progressed after 2 months. Conclusions: Though limited in patients with GBM, clinically actionable alterations are found in a small subset and can translate into meaningful clinical benefit. [Table: see text]
A phase I study of MGMT-P140K transfected hematopoetic progenitor cells (HPC) combined with TMZ/O6BG dose escalation for newly diagnosed, MGMT unmethylated glioblastoma: Tolerance and evidence of survival benefit.
Authors: Sloan Andrew E. , Roger Lisa , Murphy Chris , Reese Jane , Lazarus Hillard M. , Dropulic Boro , Gerson Stanton L. 
Published: May 2019

2062 Background: GBM is the most common malignant brain tumor with a median survival of 15 months despite surgery and radio-chemotherapy. The most important mechanism of TMZ resistance is the O6-methylguanine-DNA methyltransferase (MGMT) gene which repairs temozolamide-induced DNA methylation. The MGMT inhibitor O6-benzylguanine (BG) demonstrated efficacy in depleting MGMT and maximizing tumor response in early phase clinical trials. However, MGMT expression is also low in hematopoietic cells, so this approach led to unacceptable bone marrow toxicity and thus has been abandoned. We hypothesized that chemoprotection of hematopoietic HPC with an MGMT mutant (MGMT-P140K) characterized by normal methyltransferase activity, coupled with low affinity for BG would maximize anti-tumor response while enabling patients to tolerate TMZ & BG dose escalation with minimal toxicity. A phase I trial was performed to test this hypothesis. Methods: 10 adults with newly diagnosed MGMT unmethylated, IDH-1 WT, GBM underwent standard surgery and radiation, followed by transplantation with autologous CD34+ HPC engineered to express MGMT-P140K using a lentiviral vector. We tested tolerance and efficacy of three different paradigms for conditioning bone marrow and re-infusion of HPC. To assess chemo-protection, patients’ blood counts and transgene marking were monitored during and after treatment, as was toxicity, response, and progression-free and overall survival. Results: Treatment was moderately toxic with 3/10 patients suffering grade 3-4 hematologic toxicity; no high grade non-hematologic toxicity was observed . Viral transduction rates ranged from 3-75% and were clearly improved in Arm III utilizing BCNU conditioning and intra-patient dose escalation of TMZ/O6GB. In patients tolerating 3 cycles or more, P140K-MGMT gene markings in peripheral blood and bone marrow cells increased 3-26-fold with only mild (Grade 2-3) mylosuppression consistent with chemo-protection as hypothesized. Median PFS and OS was 22 and 31 months respectfully, and three patients in Arm III are healthy and progression free at 36-39 months. OS exceeded RPA predicted survival by 3.3-fold suggesting clinical benefit. Viral insertion site analysis demonstrate lack of clonal dominance. Conclusions: P140K-MGMT transfected HPC enables TMZ/ BG dose escalation with acceptable toxicity and increased survival in a small cohort of selected patients. A phase II study is ongoing. Clinical trial information: NCT01269424.
Prospective phase II trial in patients with first relapse of high-grade astrocytoma using TVB-2640 in combination with bevacizumab versus bevacizumab alone.
Authors: Konkel Brandon , Caflisch Laura D , Diaz Duque Adolfo Enrique , Michalek Joel , Liu Qianqian , Brenner Andrew Jacob 
Published: May 2019

2064 Background: Recurrent glioblastoma (rGBM) following chemoradiation is associated with a poor prognosis. While bevacizumab is the most common salvage therapy, responses remain brief and without an associated survival benefit. Resistance may involve overexpression of Fatty Acid Synthase (FASN). Our institution is conducting a phase 2 study of bevacizumab with FASN inhibitor TVB-2640 in patients with GBM in first relapse. Methods: This is a prospective, phase 2 study of bevacizumab with TVB-2640 in patients with GBM in first relapse. Primary end point is progression free survival (PFS). Inclusion criteria are: age ≥ 18, ECOG 0 to 2, GBM progression following standard combined modality treatment. Randomization into two arms for the first 28 days is included for exploratory biochemical analysis: patients in arm 1 receive bevacizumab every 2 weeks in combination with TVB-2640; those in arm 2 receive bevacizumab alone every 2 weeks. MR-Spectroscopy (MRS) and serum sampling for exosome analysis are obtained on patients at day 1 and 28 of first cycle. Starting on cycle 2 day 1, all patients converge to a single arm and continue to receive bevacizumab in combination with TVB-2640. Results: We have enrolled 24 patients to date; 23 have started treatment. Of those 23 patients, 10 have died, 4 have progressed but are still alive, 2 withdrew, and 7 are still active on trial. The PFS6 is and OS9 are both currently 50%, which compares favorably with historical controls. There have been no reports of grade 4 or 5 treatment-related AEs (of note, 2 deaths were thought definitely unrelated to treatment, including 1 case of intracerebral hemorrhage, and 1 case of sepsis). There have been two cases of grade 3 hand-foot syndrome thought definitely related to treatment. Updated results will include PFS, response, and biomarker analysis (exosome, MRS). Conclusions: The combination of TVB2640 with bevacizumab appears be well tolerated. PFS6 and OS9 are both currently 50%. The study has completed accrual with final data expected later in 2019. Clinical trial information: NCT03032484.