bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative radiographic analysis of phase II and III trials in recurrent glioblastoma treated with VB-111 with or without bevacizumab or bevacizumab monotherapy.
Authors: Ellingson Benjamin M. , Raymond Catalina , Yao Jingwen , Chakhoyan Ararat , Turley Dallas , Tsung Joseph , Goldman Jodi , Schlossman Jacob , Tan Caleb , Brenner Andrew Jacob , Butowski Nicholas A. , Wen Patrick Y. , Rachmilewitz Minei Tamar , Cohen Yael Chava , Harats Dror , Cloughesy Timothy Francis 
Published: May 2019

2018 Background: VB-111 is a non-replicating adenovirus carrying a pro-apoptotic transgene for TNFR1/Fas under the control of a modified murine promoter to pre-proendothelin 1. The transgene is expressed only in angiogenic endothelial cells, and therefore VB-111 results in targeted apoptosis of neovascular vessels. The current study characterizes the quantitative radiographic results and impact on OS in phase 2 and 3 trials of recurrent glioblastoma (GBM) patients treated with VB-111 with or without bevacizumab (BV) or BV monotherapy. Methods: MRI data from a phase 2 (NCT01260506) and randomized, double arm, controlled phase 3 (GLOBE; NCT02511405) trial of VB-111 in recurrent GBM were used in current study: Arm A) VB-111 monotherapy until progression followed by combination VB-111 and bevacizumab (BV) (“Primed Combination”; Phase 2; N = 24); Arm B) VB-111 in combination with BV (“Unprimed Combination”; Phase 3; N = 124) and Arm C) BV monotherapy (“Control”; Phase 3; N = 120). Contrast enhanced T1-weighted digital subtraction was used to quantify tumor volume at all time points. Results: Baseline tumor volume was not significantly different between patient cohorts (Kruskal-Wallis; P = 0.1482; median~20mL). Continuous measures of baseline tumor volume were prognostic for OS in all treatment groups when controlling for therapy and age (Cox, P < 0.001, HR = 1.02). In patients with small tumors ( < 25mL), the “primed combination” cohort (Arm A) from the phase 2 trial had a significant OS advantage compared to both upfront combination of VB-111 and BV (Arm B; P = 0.0094, HR = 0.5328; median OS = 7mo vs. 15mo) as well as BV alone (Arm C; P = 0.0248, HR = 0.5776; median OS = 8.5mo vs. 15mo). Patients with a radiographic response ( > 65% reduction) had a significant survival difference from non-responders when controlling for age, baseline tumor volume, and treatment arm ( P = 0.0014, HR = 0.5822). Notably, in responders to VB-111 monotherapy or combination therapy after priming with VB-111 exhibited characteristic, expansive areas of necrosis in areas of initial disease. Conclusions: Small recurrent tumors have a significant OS advantage when “priming” with VB-111 monotherapy prior to combination VB-111 and BV at recurrence. Patients responding to VB-111 exhibit specific imaging characteristics related to the drug mechanism of action. Clinical trial information: NCT02511405; NCT01260506.
First-in-human phase I trial of the combination of two adenoviral vectors expressing HSV1-TK and FLT3L for the treatment of newly diagnosed resectable malignant glioma: Initial results from the therapeutic reprogramming of the brain immune system.
Authors: Lowenstein Pedro R. , Orringer Daniel A , Sagher Oren , Heth Jason , Hervey-Jumper Shawn L. , Mammoser Aaron Gerald , Junck Larry , Leung Denise , Umemura Yoshie , Lawrence Theodore Steven , Kim Michelle Miran , Wahl Daniel Richard , McKeever Paul , Camelo-Piragua Sandra Ines , Lieberman Andrew , Venneti Sriram , Comba Andrea , Altshuler David , Muraszko Karin , Castro Maria 
Published: May 2019

2019 Background: This is the initial report on a first in human Phase I dose escalation trial of the combination of two adenoviral vectors expressing HSV1-TK or Flt3L for the treatment of newly diagnosed, resectable malignant gliomas. The absence of functional dendritic cells from the brain precludes anti-brain tumor immune responses. We combined tumor cytotoxicity (Ad-HSV1TK) with recruitment of dendritic cells to the brain (Ad-Flt3L) to induce an effective anti-tumor immune response. This strategy induced an efficacious, cytotoxic CD8 and CD4 T-dependent immune response in many animal models of glioma. This immune response also generated anti-tumor memory, and the capacity for neoantigen recognition. Methods: The trial was approved by FDA and all institutional cttees. Treatment was administered intraoperatively following complete glioma resection in newly diagnosed tumors. The trial consisted of vector dose escalation, starting at 1x10^9 i.u., and increasing to 1x10^11 i.u. of each vector. Dose escalation proceeded by increasing the vector dose through a total of 6 combinations administered to 6 cohorts of 3 patients each. Two cycles of 14 days each of valacyclovir were administered to activate HSV1-TK cytotoxicity. Cycle 1 starts on Day 1-3 post surgery for 14 days, and Cycle 2 on Week 8-12. Standard radiation, i.e., 60 Gy in 2 Gy fractions over 6 weeks, with concurrent temozolomide, was followed by cyclic temozolomide. Results: Examination of tumor samples at primary resection and first recurrence show an increase in the infiltration of inflammatory cells. The experimental treatment was well tolerated. At this time the MTD has not been reached. There were approx. 248 AEs, and 26 SAEs; these have not been linked to treatment. At this time the MTD has not been reached. A secondary outcome is overall survival. Preliminary analysis of partial data may suggest that the combined viral vector therapy may provide a clinically significant survival. Conclusions: Our results show for the first time that reprogramming of the host’s brain immune system to recognize gliomas reveals a new approach for the treatment of highly malignant brain tumors. Clinical trial information: NCT01811992.
Full enrollment results from an extended phase I, multicenter, open label study of marizomib (MRZ) with temozolomide (TMZ) and radiotherapy (RT) in newly diagnosed glioblastoma (GBM).
Authors: Mason Warren P. , Kesari Santosh , Stupp Roger , Aregawi Dawit Gebremichael , Piccioni David Eric , Roth Patrick , Desjardins Annick , Reich Steven D. , Casadebaig Marie-Laure , Elias Ileana , Winograd Benjamin , Levin Nancy , Bota Daniela Annenelie 
Published: May 2019

2021 Background: Proteasome inhibition sensitizes glioma cells to TMZ and RT, providing a novel therapeutic strategy for GBM. MRZ, an irreversible, brain-penetrant, pan-proteasome inhibitor with anti-glioma activity was combined with standard TMZ/RT → TMZ in newly diagnosed GBM (NCT02903069), to determine the recommended dose (RD). The primary endpoint of this expanded phase 1 trial was toxicity, with secondary endpoint of OS. Methods: Patients were enrolled in separate cohorts (TMZ/RT+MRZ→TMZ+MRZ, N=15; TMZ/RT→TMZ+MRZ, N=18) in dose-escalation (3+3 design), followed by dose-expansion (N=20) with TMZ/RT+MRZ at RD → TMZ+MRZ at RD. A separate cohort received TMZ/RT→TMZ+MRZ at RD with Tumor Treating Fields (Optune, N=13). MRZ was infused IV (10 min at 0.55, 0.7, 0.8, and 1.0 mg/m2) on Days 1, 8, 15, 29, 36 (42-day TMZ/RT+MRZ cycle) and Days 1, 8, 15 (28-day TMZ+MRZ cycle). Results: 66 patients treated; median age 58 years, 68% male, 50% receiving corticosteroid at baseline, 52% unmethylated MGMT. Dose-limiting toxicities (DLTs) in dose-escalation cohorts: 1 (fatigue) at 0.7 mg/m2 MRZ, 5 (ataxia/diarrhea; ataxia/confusion; myocardial infarction, delirium/ataxia; ataxia/fatigue) in 1.0 mg/m2 cohorts. MRZ demonstrated a steep dose-response with treatment-emergent adverse events (TEAEs)/DLTs predominately CNS AEs (Grade ≥3 TEAEs in 12 of 12 patients at 1.0 mg/m2 vs 22 of 41 patients at ≤0.8 mg/m2); the RD for MRZ was determined to be 0.8 mg/m2. Most common TEAEs (all grades): fatigue, nausea (both 70%), hallucination (54%), vomiting (53%), headache (47%), confusional state (33%), ataxia, constipation, muscular weakness (all 29%). Conclusions: CNS TEAEs were short-lasting, reversible and ameliorated by early dose reductions (29% patients dose-reduced), allowing patients to remain on treatment. For patients receiving MRZ with TMZ/RT→TMZ (N=35), the median OS was 14.8 months (17 deaths, median follow-up 14.3 months), and 7 patients remain active (Cycles 11-23). The MRZ RD + TMZ/Optune combination was tolerated, with 4 of 13 patients treated on this arm remaining active. An international Phase 3 trial (EORTC 1709-BTG/CCTG CE.8, NCT03345095) is ongoing. Clinical trial information: NCT02903069.
DGM1 may serve as a novel genetic biomarker of response to enzastaurin in glioblastoma.
Authors: Butowski Nicholas A. , Shazer Ronald L. , Sun Hong , Han Isabel , Jivani Manoj A. , Luo Wen 
Published: May 2019

2023 Background: Despite countless clinical trials being conducted, little has changed over the last decade in the chemotherapies available for glioblastoma (GBM) with survival remaining poor. Meaningful advances in treating this deadly malignancy may rely on precision medicine. We discovered a novel pharmacogenomic biomarker for enzastaurin (enz) in treating lymphoma (lymph). We evaluated if this biomarker can be used to predict enz response in GBM. Methods: Biomarker discovery was performed by a genome-wide screen using DNA extracted from blood samples from a ph 3 enz lymph trial and confirmed in an independent ph 2 enz lymph trial. The biomarker was then evaluated for its predictability in GBM using the archived DNA samples from a prior ph 1/2 enz GBM trial. Results: A novel biomarker, Denovo Genomic Marker 1 (DGM1), a germline polymorphism on chromosome 8, was found to be highly correlated with response to enz in the two lymph trials. Using DNA extracted from blood of pts from the single-arm ph 1/2 study of newly diagnosed GBM receiving enz added to radiation and temozolomide (tmz), we found median OS for DGM1+ pts treated with enz was 18 mon vs 12.8 mon for DGM1- pts, HR (95% CI) 0.68 (0.25, 1.81), p = 0.12. In addition, we found pts in the GBM study receiving a mean daily dose of enz ≥ 245 mg had an OS of 19.8 mon vs 14.9 mon for pts receiving a mean daily dose of < 245 mg [HR (95% CI) 0.55 (0.34, 0.90)]; enz 500 mg/day was used in the lymph studies. Conclusions: These data are supportive of DGM1 as a potentially predictive biomarker for enz response in both lymph and GBM. There is an ongoing biomarker-driven pivotal ph 3 study in lymph at 500 mg/day, and DGM1 in GBM will be further evaluated in a planned randomized ph 2b study in newly diagnosed GBM with 500 mg/day of enz in combination with tmz.
Safety and activity of a first-in-class oral HIF2-alpha inhibitor, PT2385, in patients with first recurrent glioblastoma (GBM).
Authors: Strowd Roy E. , Ellingson Benjamin M. , Wen Patrick Y. , Ahluwalia Manmeet Singh , Piotrowski Anna F. , Desai Arati Suvas , Clarke Jennifer Leigh , Lieberman Frank S. , Desideri Serena , Nabors Louis B. , Ye Xiaobu , Grossman Stuart A. 
Published: May 2019

2027 Background: Hypoxia inducible factor 2-alpha (HIF2a) mediates cellular responses to hypoxia and is overexpressed in GBM. PT2385 is an oral HIF2a inhibitor with in vivo activity against GBM. Methods: A two-stage single-arm open-label phase II study of adults with first recurrent GBM following chemoradiation with measurable disease was conducted through the Adult Brain Tumor Consortium. PT2385 was administered at the phase II dose (800 mg b.i.d.). The primary outcome was objective radiographic response (CR+PR); secondary outcomes were safety and survival. Exploratory objectives included PK (day 15 Cmin), PD, and pH-weighted amine-CEST MRI to quantify tumor acidity at baseline and explore associations with drug response. Stage 1 enrolled 24 patients with early stoppage for ≤1 response. Results: Of the 24 patients, mean age was 61±11 years, median KPS 80, MGMT promoter methylated in 46%. PT2385 was well tolerated. Grade ≥3 drug-related AEs were hypoxia (n = 2), anemia (1), hyperglycemia (1), hyponatremia (2) and lymphopenia (2). No objective radiographic responses were observed; median PFS was 1.8 months (95%CI 1.6-3.1). Drug exposure varied widely (Table) and did not differ by corticosteroid use (p = 0.12), antiepileptics (p = 0.09), or sex (p = 0.37). Patients with high systemic exposure had significantly longer PFS (6.7 vs 1.8 months, 0.009). Non-enhancing infiltrative disease with high acidity gave rise to recurrence. Baseline acidity correlated significantly with treatment duration (R2= 0.49, p = 0.017). Conclusions: Drug exposure to PT2385 was variable. Signals of activity were observed in GBM patients with high systemic exposure and acidic (e.g. hypoxic) lesions on baseline imaging. A second-generation HIF2a inhibitor is being studied. Clinical trial information: NCT03216499. [Table: see text]
Survival outcomes in glioma patients with noncanonical IDH mutations: Beyond diagnostic improvements.
Authors: Franceschi Enrico , De Biase Dario , Pession Annalisa , Tosoni Alicia , Paccapelo Alexandro , Visani Michela , Tallini Giovanni , Argento Chiara Maria , Urbini Benedetta , Bartolini Stefania , Brandes Alba Ariela 
Published: May 2019

2028 Background: According to the 2016 WHO classification of Central Nervous System tumors, the assessment of exon 4 mutations in IDH1 or IDH2 genes is an essential step in the characterization of gliomas. The R132H mutation is the most frequent alteration in IDH1 gene, however other non-canonical IDH mutations have been identified. The aim of this study was to evaluate the prognostic role of IDH non-canonical mutations. Methods: We analyzed our institutional data warehouse for all consecutive patients (pts) with newly diagnosed, histologically proven grade II – IV IDH mutant gliomas. IDH sequencing was performed using the 454 GS-Junior next generation sequencer (NGS) (Roche Diagnostic, Mannheim, Germany). All analyses were performed on DNA from formalin fixed and paraffin embedded (FFPE) specimens. Results: The analysis included 493 pts with IDH mutations. We found 279 (56.6%) grade 2, 173 grade 3 (35.1%) gliomas, and 41 (8.3%) IDH mutant glioblastoma. Canonical IDH1 R132H mutation was found in 428 pts (86.8%). The remaining pts showed IDH2 (3.9%) or IDH 1 non-canonical mutations (mainly R132C, R132G, R132S – 9.3%). Median follow-up time was 80.5 months. Pts with non-canonical mutations showed a younger median age (32 vs 39 years, p < 0.001). Other clinical characteristics and treatments were similar across IDH groups. Median survival was 145 months (95%CI: 137.7 - 152.9) and 198.6 (95%CI 155.2– 242.1) in patients with IDH R132H and non-canonical mutations, respectively (p = 0.013). In multivariate analysis grading (p < 0.001), extent of surgery (p < 0.001), 1p19q codeletion (p = 0.003) and presence of non-canonical mutations (p = 0.022) showed a significant role for improved survival. Conclusions: Detecting non-canonical IDH1 mutations is essential for diagnosis and for prognosis in patients with gliomas. Differential enzymatic activity of non-canonical IDH1 mutations, resulting in different levels 2-hydroxyglutaratecould be the reason of improved survival.
Glioblastoma gene expression subtypes and correlation with clinical, molecular and immunohistochemical characteristics in a homogenously treated cohort: GLIOCAT project.
Authors: Pineda Estela , Esteve-Codina Anna , Martinez-Garcia Maria , Alameda Francesc , Carrato Cristina , Arpi Oriol , Aldecoa Iban , Menendez Silvia , Ribalta Teresa , Vidal Sarro Noemi , Berron Sonia Del Barco , Estival Anna , Gallego Oscar , Gil Gil Miguel J. , Mesia Barroso Carlos , Craven Jordi , Villa Salvador , Fuentes Rafel , de la Iglesia Núria , Balana Carmen 
Published: May 2019

2029 Background: Glioblastoma (GBM) gene expression subtypes have been described in last years, data in homogeneously treated patients is lacking. Methods: Clinical, molecular and immunohistochemistry (IHC) analysis from patients with newly diagnosed GBM homogeneously treated with standard radiochemotherapy were studied. Samples were classified based on the expression profiles into three different subtypes (classical, mesenchymal, proneural) using Support Vector Machine (SVM), the K-nearest neighbor (K-NN) and the single sample Gene Set Enrichment Analysis (ssGSEA) classification algorithms provided by GlioVis web application. Results: GLIOCAT Project recruited 432 patients from 6 catalan institutions, all of whom received standard first-line treatment (2004 -2015). Best paraffin tissue samples were selected for RNAseq and reliable data were obtained from 124. 82 cases (66%) were classified into the same subtype by all three classification algorithms. SVM and ssGEA algorithms obtain more similar results (87%). No differences in clinical variables were found between the 3 GBM subtypes. Proneural subtype was enriched with IDH1 mutated and G-CIMP positive tumors. Mesenchymal subtype (SVM) was enriched in unmethylated MGMT tumors (p = 0.008), and classical (SVM) in methylated MGMT tumors (p = 0.008). Long survivors ( > 30 months) were rarely classified as mesenchymal (0-7.5%) and were more frequently classified as Proneural (23.1-26.). Clinical (age, resection, KPS) and molecular ( IDH1, MGMT) known prognostic factors were confirmed in this serie. Overall, no differences in prognosis were observed between 3 subtypes, but a trend to worse survival in mesenchymal was observed in K-NN (9.6 vs 15 ). Mesenchymal subtype presented less expression of Olig2 (p < 0.001) and SOX2 (p = 0.003) by IHC, but more YLK-40 expression (p = 0.023, SVM). On the other hand, classical subtype expressed more Nestin (p = 0.004) compared to the other subtypes (K-NN). Conclusions: In our study we have not found correlation between glioblastoma expression subtype and outcome. This large serie provides reproducible data regarding clinical-molecular-immunohistochemistry features of glioblastoma genetic subtypes.
Cancer differentiation analysis technology as a novel technology for cerebral cancer screening.
Authors: Tao Hongmei , Tang Xing , Lin Yue , Yu Chris Chang , Du Xuedong 
Published: May 2019

2040 Background: While the current cancer screening methods mostly failed to detect cerebral cancer, a novel, promising technology named cancer differentiation analysis (CDA) technology has been developed to measure novel bio-physical properties to obtain valuable multi-level and multi-parameter information including protein, cellular and molecular level information. Initial results showed that CDA technology is capable of detecting cerebral cancer with a high degree of sensitivity and specificity. Methods: In this study, samples from 78 cerebral cancer patients and 321 healthy individuals were measured. Peripheral blood of each individual was drawn in EDTA tubes. One class of bio-physical property in blood samples was utilized for CDA tests. CDA data were conducted using SPSS, and the results were shown in table. Results: The average CDA values of cerebral cancer and control groups were 52.30 and 33.38 (rel. units) respectively. The results indicated that cerebral cancer could be significantly distinguished from the control (p < 0.001). Area under ROC curve (AUC) was 0.980, and sensitivity and specificity was 92.3% and 96.6% respectively. Conclusions: Initial results showed that CDA technology could effectively distinguish cerebral cancer from healthy individuals. As a novel bio-physical based cancer detection approach with multi-level and multi-parameter expressions, CDA could be a potential candidate for cerebral cancer screening. Results from Statistical Analysis of CDA. [Table: see text]
Health-related quality of life (HRQL) in VERTU: A randomized phase II trial of veliparib (V), radiotherapy (RT), and temozolomide (TMZ) for newly diagnosed MGMT unmethylated (uMGMT) glioblastoma (GBM).
Authors: Sim Hao-Wen , Barnes Elizabeth , Lwin Zarnie , Rosenthal Mark , Wheeler Helen , Koh Eng-Siew , Foote Matthew C. , Fisher Lauren , Leonard Robyn , Hall Merryn , Simes John , Khasraw Mustafa 
Published: May 2019

2042 Background: The VERTU trial (ANZCTR #ACTRN12615000407594) compared Arm A (standard of care) = RT (60Gy/30 fractions) + TMZ (75mg/m2 daily) followed by TMZ (150–200mg/m2 D1–5) every 28 days for 6 cycles vs Arm B (experimental arm) = RT (60Gy/30 fractions) + V (200mg PO BID) followed by TMZ (150–200mg/m2 D1–5) + V (40mg PO BID, D1–7) every 28 days for 6 cycles in pts with newly diagnosed centrally determined uMGMT GBM. To ensure that veliparib was not associated with clinical detriment, serial HRQL assessments were performed for comparison as a secondary objective. Methods: Pts completed the EORTC quality of life core questionnaire (QLQ-C30) and brain cancer module (BN20) every 4 weeks (w) (baseline: w0; concurrent: w4,8; adjuvant: w10,14,18,22,26,30). Based on relevance to GBM patients, 5 HRQL scales (global health [GH], physical functioning [PF], social functioning [SF], motor dysfunction [MD] and communication deficit [CD]) were pre-selected for primary analysis. Maximum change from baseline score (clinically relevant deterioration/improvement defined as ≥10-point change) during the progression-free period, and deterioration-free survival (time to deterioration/progression/death) were evaluated. Results: Patient characteristics were well-matched (Arm A: N = 41, median age = 62, male = 68%, ECOG 0 = 66%, macroscopic resection = 88%; Arm B: N = 84, median age = 60, male = 70%, ECOG 0 = 65%, macroscopic resection = 86%). Almost all completed at least one HRQL assessment (98%). HRQL assessments during the progression-free period were completed in 87% (Arm A) and 90% (Arm B) of cases. For Arm A vs B, the proportion of patients who experienced a deterioration in GH (59% vs 64%, p = 0.69), PF (53% vs 53%, p > 0.99), SF (46% vs 53%, p = 0.56), MD (63% vs 58%, p = 0.70) and CD (45% vs 46%, p > 0.99) were similar. Deterioration-free survival was not statistically different for any HRQL item. Conclusions: The addition of veliparib to standard of care for newly diagnosed uMGMT GBM does not appear to compromise HRQL. This would support the primary efficacy analysis of the VERTU trial. Clinical trial information: ACTRN12615000407594.