bluuebunny/crossref_metadata_2025_split huggingface dataset:
MRI changes in patients with newly diagnosed glioblastoma treated as part of a phase II trial with bavituximab, radiation, and temozolomide.
Authors: Ly Ina , Cardona Jonathan , Lou Kevin , Beers Andrew , Chang Ken , Brown James , Reardon David A. , Arrillaga-Romany Isabel , Forst Deborah Anne , Jordan Justin T , Lee Eudocia Quant , Dietrich Jorg , Nayak Lakshmi , Wen Patrick Y. , Chukwueke Ugonma Nnenna , Batchelor Tracy , Curry William T. , Kalpathy-Cramer Jayashree , Gerstner Elizabeth Robins 
Published: May 2020

2546 Background: Glioblastoma and tumor endothelial cells express phosphatidylserine (PS), a highly immunosuppressive membrane phospholipid. Bavituximab – a chimeric monoclonal antibody – binds to β2-glycoprotein 1 (β2-GP1) to form a complex of β2-GP1 with PS, resulting in immune activation against tumor cells and anti-angiogenic effects. Phase I/II trials in other solid cancers demonstrated response rates up to 75% when bavituximab was given with cytotoxic chemotherapy. Pre-clinical data in glioblastoma models suggested synergistic effects of PS blockade, radiation, and temozolomide. Methods: 33 adult patients with IDH-wild-type, MGMT-methylated or -unmethylated newly diagnosed glioblastoma were enrolled in this phase II trial (NCT03139916) and received 6 weeks of chemoradiation, followed by 6 cycles of adjuvant temozolomide (C1-C6 aTMZ). Bavituximab (3 mg/kg) was given weekly, starting week 1 of chemoradiation, for 18 weeks with the option to continue if tolerated. Physiologic MRIs were performed pre-treatment, pre-C1, pre-C3, and pre-C5 aTMZ. Within the enhancing tumor region, median tumor Ktrans (reflecting vascular permeability) and relative cerebral blood flow (rCBF) were measured. Median percent changes during treatment were compared to pre-treatment values. Results: Median progression-free survival (mPFS) was 8 months. Based on a median overall survival (mOS) of 17.1 months, patients were categorized into above-median survivors (AMS) and below-median survivors (BMS). All patients had pre-treatment scans. 31 had evaluable pre-C1, 25 had pre-C3, and 7 had pre-C5 scans. Compared to BMS, AMS had a greater reuction in enhancing tumor volume and rCBF, and a greater increase in Ktrans during treatment (table). One patient remains on study; 23 patients have died. Bavituximab was well tolerated. Conclusions: mPFS and mOS in patients treated with bavituximab, radiation and temozolomide were comparable to standard chemoradiation and aTMZ. Lower rCBF in AMS may reflect decreased tumor perfusion while higher Ktrans could imply enhanced drug delivery to the tumor. Bavituximab induces changes in tumor vasculature that may improve survival in a subset of patients. Clinical trial information: NCT03139916 . [Table: see text]
Association of peripheral blood CD4+ T-cell depletion under temozolomide with inferior survival of patients with IDH wildtype glioblastoma.
Authors: Weller Michael , Terksikh Ekaterina , Silginer Manuela , Krieg Carsten , Roth Patrick , Becher Burkhard , Wirsching Hans-Georg 
Published: May 2020

2548 Background: Standard first line chemoirradiation with temozolomide is associated with distinctive peripheral blood immune cell profiles in IDH wildtype glioblastoma. Whether such profiles at recurrence are associated with survival has not been studied in detail. Methods: Peripheral blood mononuclear cells of 21 healthy donors and of 91 patients with IDH wildtype glioblastoma were analyzed by flow cytometry at 1st recurrence. Patients received either (i) standard chemoirradiation with temozolomide (TMZ) followed by dose-intensified TMZ at first recurrence within the phase II trial DIRECTOR (N = 52) or (ii) hypofractionated radiotherapy with or without bevacizumab (N = 39) followed by investigators’ choice within the phase II trial ARTE. Patients were classified based on unsupervised analyses of PBMC profiles at 1st recurrence. Associations with survival were explored in multivariate Cox models controlling for established prognostic and predictive factors. Results: At 1st recurrence, two patient clusters were identified in the DIRECTOR cohort which differed in CD4+ T-cell fractions, but not with respect to CD8+ T-cells, CD4+;CD25+;FoxP3+ regulatory T-cells, B-cells or monocytes. The composition of CD4+, CD8+ or regulatory T-cell fractions was similar in both clusters. All control samples clustered with the CD4high cluster. Patients in both clusters did not differ by established prognostic factors, including age, O6-methylguanine-DNA-methyl-transferase ( MGMT) gene promoter methylation, tumor volume, Karfnosky performance score or steroid use. Progression-free survival was similar (CD4high vs CD4low 2.1 vs 2.4 months, p = 0.19), whereas post-recurrence overall survival was longer among the CD4high cluster (12.7 vs 8.7 months, p = 0.004). At 2nd recurrence after dose-intensified TMZ re-challenge, monocyte fractions increased, whereas memory CD4+ T-cell fractions decreased. Higher memory CD4+ fractions were associated with longer overall survival at 2nd recurrence (p = 0.004). The reported associations were retained in multivariate Cox models controlling for established prognostic factors. In the ARTE cohort, CD4+ T cell fractions at 1st recurrence did not differ compared to diagnosis (p = 0.91) and there were no associations with bevacizumab (p = 0.28) or survival (p = 0.74), supporting that the effects observed in the DIRECTOR cohort were driven by TMZ. Conclusions: We conclude that TMZ-associated memory CD4+ T-cell depletion may have deteriorating effects on the survival of glioblastoma patients.
Lymphocyte-activation gene 3 (LAG-3) expression in the inflammatory microenvironment of glioma.
Authors: Mair Maximilian , Kiesel Barbara , Feldmann Katharina , Widhalm Georg , Dieckmann Karin , Woehrer Adelheid , Muellauer Leonhard , Preusser Matthias , Berghoff Anna Sophie 
Published: May 2020

2553 Background: The blockade of lymphocyte-activation gene 3 (LAG-3), an inhibitory receptor on tumor-infiltrating lymphocytes, is currently under investigation in many extracranial tumor entities. Methods: 54 patients with diffuse glioma were included: 35 patients with glioblastoma (GBM, median age at diagnosis: 61 years) as well as 14 with WHO grade II and 5 with WHO grade III glioma (lower-grade glioma, LGG, median age at diagnosis: 45 years). Isocitrate dehydrogenase 1/2 mutations (IDH-mt) were present in 17/54 patients and 37/54 patients had IDH wildtype (IDH-wt) tumors. LAG-3 expression on tumor-infiltrating lymphocytes (TILs) was analyzed by immunohistochemistry (monoclonal anti-LAG-3 antibody, clone 17B4, LSBio Inc.). Results: LAG-3+ TILs could be observed in 5/54 (9.3%) samples, while CD3+ TILs were present in 32/54 (59.3%) and CD8+ TILs in 24/54 (44.4%) samples. Only IDH-wt glioma presented with LAG-3+ TILs (p = 0.168). Samples with LAG-3+ TILs presented with a numerical trend towards higher presence of CD3+ (5/27 CD3+ vs. 0/22 CD3−, p = 0.072) and CD8+ TILs (4/24 CD8+ vs. 1/30 CD8−, p = 0.159). 4/7 (57.1%) samples presenting with PD-1+ TILs also presented with LAG-3+ TILs (p = 0.001). Furthermore, glioma samples with LAG3+ TILs presented with higher expression of PD-L1 (median: 1% vs. 0%; p = 0.166). There was no difference in overall survival (OS) according to LAG-3+ TIL infiltration (median OS in LAG-3+: 21.7 months vs. LAG-3−: 41.4 months, p > 0.05). Conclusions: LAG-3+ TILs are rarely observed in IDH-wt and absent in IDH-mt glioma. Gliomas with an active inflammatory microenvironment present more frequently with LAG3+ TILs. The diverse composition of the inflammatory microenvironment and particular inflammatory subgroups should be considered in future clinical trials on immune-modulating therapies in glioma.
Ibrutinib-based combination therapy exhibited therapeutic benefit in newly diagnosed primary central nervous system lymphoma.
Authors: Chen Feili , Pang Diwen , Guo Hanguo , Ou Qiuxiang , Wu Xue , Jiang Xinmiao , Wei Xiaojuan , Liu Sichu , Huang Ling , Liang Zhanli , Li Wenyu 
Published: May 2020

2556 Background: Ibrutinib has shown single-agent activity in relapse/refractory (R/R) primary central nervous system lymphoma (PCNSL), and the high dose methotrexate (HD-MTX) has been the backbone of treatment of de-novo PCNSLs. Combination therapy of HD-MTX and ibrutinib has recently shown activity in R/R PCNSLs. Methods: Eleven newly diagnosed PCNSL patients who underwent combination therapy of HD-MTX and ibrutinib were analyzed for treatment response and safety profile. HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses. Ibrutinib was held on days of HD-MTX infusion until HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. Patients’ clinicopathologic characteristics were retrospectively reviewed and genomic traits were further analyzed. Results: Nine out of 11 patients have completed the induction phase of ibrutinib-based combination therapy and received ibrutinib maintenance in addition to two patients whose disease progressed during the therapy. An objective response rate (ORR) of 82% (9/11) was observed, including 7 patients with complete response (CR, 64%) and 2 patients with partial response (PR, 18%). The median progression-free survival (PFS) was 7.4 months while the median overall survival (OS) was not reached. The combination therapy of HD-MTX and ibrutinib was well tolerated and has acceptable safety. In addition, the presence of ctDNA in cerebrospinal fluid (CSF) samples closely correlated with tumor response. Sustained tumor responses were associated with the clearance of ctDNA from the CSF. Conclusions: Combination of ibrutinib and HD-MTX has acceptable safety and has demonstrated anti-tumor activity in newly diagnosed de-novo PCNSL patients. The detection of ctDNA in CSF is feasible for monitoring tumor burden in PCNSL patients.
Clinical, radiologic & prognostic profile of IDH wild type diffuse astrocytic glioma with molecular features of glioblastoma.
Authors: Akintola Oluwatosin , Samore Wesley , Martinez-Lage Alvarez Maria , Gerstner Elizabeth Robins 
Published: May 2020

2557 Background: In 2018, The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) recommended that IDH-wildtype diffuse astrocytic glioma Grade II/III with either EGFR amplification, combined whole chromosome 7 gain and whole chromosome 10 loss (+7/−10), or TERT promoter mutation should receive an integrated histological and molecular grade classification: Diffuse astrocytic glioma, IDH-wildtype with molecular features of glioblastoma, WHO grade IV. The natural history, radiologic characteristics and standard management for these patients has not been well described. They are typically excluded from clinical trials for WHO Grade IV gliomas. Methods: Adults diagnosed at Massachusetts General Hospital with IDH wildtype diffuse astrocytoma and EGFR amplification or TERT promoter mutation from 2011-2019 were identified. Demographics, functional status, radiologic features, MGMT promoter methylation status, time to progression, and overall survival were collected retrospectively. Qualitative MRI data was analyzed using the VASARI feature set. Response assessment was performed using the RANO criteria. Results: 50 patients were identified (table). 37/50 patients received standard Stupp protocol, 2/50 received hypofractionated radiotherapy with temozolomide, 6/50 received radiotherapy alone, and 1 patient received a MEK inhibitor. None were enrolled in clinical trials at diagnosis. mPFS was 10 months in the 47/50 with confirmed progression and mOS in the patients with confirmed deaths (40/50) was 17.5 months (4-47). 9/50 patients are alive with survival ranging 6-52 months. Conclusions: Outcomes for patients with molecularly defined GBM were variable. Analysis of the cohort to characterize factors that led to the observed variability is in progress. More studies on molecularly defined glioblastomas are required to better understand their behavior and to provide guidance for their inclusion or exclusion in clinical trials. [Table: see text]
A pilot study of levetiracetam as a sensitizer of temozolomide for newly diagnosed glioblastoma: A prospective, open-label, phase II study (KBTS-1601 study).
Authors: Kim Chae-Yong , Hwang Kihwan , Chang Jong Hee , Kang Seok-Gu , Jung Tae-Young , Kim Jeong Hoon , Kim Se-Hyuk , Kang Shin-Hyuk , Hong Yong-Kil , Kim Tae Min , Choi Byung Se , Kim YuJung , Choe Ghee Young 
Published: May 2020

2560 Background: We evaluated the survival benefit of levetiracetam as a chemosensitizer of temozolomide for patients with newly diagnosed glioblastoma. Methods: This was an open-label, multicenter, phase II study (NCT02815410). Eligible patients were aged 18 years or older and had newly diagnosed glioblastoma with an ECOG performance status of 0-2. All patients received radiotherapy with concurrent temozolomide (75 mg/m2/day) followed by adjuvant temozolomide (150-200 mg/m2/day for 5 days during six 28-day cycles). The first dose of levetiracetam was given just after the surgery at 250mg orally twice a day and increased up to 500mg twice a day prior to radiation. This prospective study was designed to test whether levetiracetam in conjunction with temozolomide improved survival. The historical control group was based on data from a study by Gwak et al. for Korean patients with newly diagnosed glioblastoma with a median overall survival(OS) of 17.5 months and a median progression-free survival (PFS) of 10.1 months. Results: Forty-six patients were enrolled between August 2016 and January 2019. The median follow-up duration was 24.9 months (range, 7.9-35.5). All patients completed standard radiation therapy with temozolomide, and 39 (84.8%) patients completed six cycles of adjuvant temozolomide. Median overall survival (OS) was 30.0 months, and median PFS was 15.0 months. OS at 6, 12, and 24 months was 100%, 91.3%, and 60.7%, respectively. PFS at 6, 12, and 24 months was 93.2%, 65.3%, and 22.6%, respectively. Conclusions: Addition of levetiracetam during concurrent and adjuvant temozolomide along with radiotherapy in patients with newly diagnosed glioblastoma may result in improved outcomes compared to historical data and merits further study. Clinical trial information: NCT02815410 .
Survival of subjects with recurrent glioblastoma receiving intratumoral administration of controlled IL-12 with limited exposure to dexamethasone.
Authors: Lukas Rimas Vincas , Kurz Sylvia Christine , Yu John , Landolfi Joseph C. , Rao Ganesh , Amidei Christina , Buck Jill Yannetti , Hadar Nira , Estupinan Taylor , Miao John , Loewy John W. , Wang Yunxia , Demars Nathan A. , Gelb Arnold Bruce , Cooper Laurence JN 
Published: May 2020

2564 Background: Interleukin-12 (IL-12) results in anti-tumor responses in preclinical models but requires tightly controlled production to achieve safety and elicit immune system activation to realize efficacy. A phase 1 “main study” (NCT02026271) enrolled subjects with Grade III or IV gliomas who at the time of resection received intratumoral administration of a replication-deficient adenovirus expressing IL-12 under control of a transcriptional switch (Ad-RTS-hIL-12, Ad) regulated by veledimex (V), referred to as “Controlled IL-12”. It was anticipated that dexamethasone (dex), a lymphocytotoxic corticosteroid used to control edema, might diminish response to immunotherapies. We report updated findings from a substudy of subjects who were dex-free during the 4 weeks prior to Ad administration. Methods: Multicenter, phase 1 substudy (NCT03679754) that assesses safety and tolerability of Controlled IL-12 by local injection (Day 0, time of resection) of Ad (2 x 1011 viral particles) + V (20 mg PO QD x15 doses, Days 0-14) in subjects that were bevacizumab naïve and not receiving dex 4 weeks prior to Ad. Results: 36 subjects were treated. Of the 36, a majority received low-dose corticosteroids (≤ 20 mg dex total during V) as compared with the main study (75% vs 40%). More subjects in the substudy as compared with the main study had multifocal vs. unifocal disease (39% vs 7%). The safety profile was similar for both. Adverse reactions were mild to moderate and were manageable and reversable upon withholding V. Activation of the switch in both the main study and substudy (V 20 mg; n = 51) resulted in increased mean peak values (Day 0-28) of serum IL-12 (25.8 vs. 20.4 pg/mL) and IFN-g (57.0 vs. 39.5 pg/mL). Initial median overall survival (mOS) (unifocal, ≤ 20 mg dex cumulative, n = 20) was 16.2 (8.9, 18.5) mons (mean follow-up 12.3 mons) (Neuro Oncol 2019; 21 [suppl_6]:vi5). mOS including the impact of dex and key subject characteristics from the two studies (n = 51) will be updated and tumor response data will be provided. Conclusions: Monotherapy with Controlled IL-12 resulted in sustained increase in serum recombinant IL-12 and downstream endogenous IFN-g. There is evidence of immune-mediated anti-tumor effects which is associated with increased mOS as compared with historical controls. Follow up will investigate the adverse impact of dex, as well as the effect of additional subject characteristics ( e.g., unifocal vs. multifocal disease) on mOS. Clinical trial information: NCT03679754 .
Molecular predictors of response to selinexor in recurrent glioblastoma (GBM).
Authors: Walker Christopher James , Shen Yao , Mau-Sørensen Morten , Wen Patrick Y. , Van Den Bent Martin J. , Plotkin Scott Randall , Walenkamp Anna Maria Elisabeth , Green Adam , Califano Andrea , Chang Hua , Henegar Leah , Shacham Sharon , Alvarez Mariano J , Landesman Yosef , Lassman Andrew B. 
Published: May 2020

2565 Background: The nuclear export protein exportin 1 (XPO1) is overexpressed in many cancers, including GBM. Selinexor is an inhibitor of XPO1 that crosses the blood-brain-barrier and targets cancer cells by sequestering tumor suppressor proteins and oncoprotein mRNAs in the cell nucleus, inducing cancer cell apoptosis. Selinexor is FDA approved for treatment of patients (pts) with refractory multiple myeloma and is under evaluation for GBM. Methods: We previously reported encouraging results from a phase II clinical trial of selinexor for molecularly unselected pts with recurrent GBM (ASCO 2019). On available pre-treatment archival tumor tissue from 57 cases, we performed DNA exome and RNA transcriptome sequencing to use both gene mutations and expressions for exploring molecular correlates of response in selinexor treated pts, in a hypothesis generating, post-hoc, exploratory analysis. Pts with inadequate drug exposure were excluded ( < 21 days or < 3 doses). We compared OS and PFS between mutated and wild-type patients for genes mutated in at least 5 cases. RNAseq data were used to infer differential protein activities between patients with selinexor sensitive disease (defined as best response of partial or complete response, n = 7) vs. resistant disease (defined as progressive disease as best response, n = 23). Results: Two mutated genes were associated with longer survival in selinexor treated pts: DOCK8 (n = 7; progression free survival [PFS], P = 0.013, hazard ratio [HR] = 3.75 [1.32-10.62]; overall survival, P = 0.009, HR = 15.39 [2.00-118.34]) and PDX1 (n = 5, PFS, P = 0.014, HR = 4.468 [1.361-14.670]). Other commonly mutated genes in glioma, including IDH1 (n = 9) were observed but not associated with survival. Protein activities inferred from RNA sequencing data were also correlated with response to selinexor. In a machine learning model, ZC3H12A (also called MCPIP-1), a negative regulator of inflammation; RAB43, a member of the RAS family that binds GTP and regulates vesicle trafficking, and SOCS3, a suppressor of cytokine signaling that can antagonize JAK/STAT signaling and repress innate immunity, predicted clinical benefit from selinexor (area under the ROC curve from leave one out cross validation = 0.89, permutation test P < 0.04). Conclusions: DOCK8 and PDX1 mutations were favorable prognostic factors in selinexor treated pts. Activity of three proteins (ZC3H12A, RAB43, and SOCS3) predicted clinical benefit from selinexor. Further studies with more pts are required to validate our findings. ClinicalTrials.gov: NCT01986348
A phase I, first-in-human, open-label, dose-escalation study of MGD013, a bispecific DART molecule binding PD-1 and LAG-3, in patients with unresectable or metastatic neoplasms.
Authors: Luke Jason J. , Patel Manish R. , Hamilton Erika Paige , Chmielowski Bartosz , Ulahannan Susanna Varkey , Kindler Hedy L. , Bahadur Shakeela Wazeen , Clingan Philip R. , Mallesara Girish , Weickhardt Andrew James , Currence Scott , Xu Linzhi , Kaul Sanjeev , Chen Francine , Moore Paul A. , Bonvini Ezio , Sumrow Brad , Blumenschein George 
Published: May 2020

3004 Background: MGD013 is an investigational, first-in-class, Fc-bearing bispecific tetravalent DART molecule designed to bind PD-1 and LAG-3 and sustain/restore the function of exhausted T cells. MGD013 demonstrates ligand blocking properties consistent with anti-PD-1 and anti-LAG-3 benchmark molecules, and improves T cell responses beyond that observed with benchmark or component antibodies alone or in combination. Methods: This study characterizes the safety, tolerability, dose-limiting toxicities, maximum tolerated dose (MTD), PK/PD, and antitumor activity of MGD013 in patients (pts) with advanced solid and hematologic malignancies. Sequential single-pt cohorts were treated with escalating flat doses of MGD013 (1-1200 mg IV every 2 weeks), followed by a 3+3 design. Tumor-specific expansion cohorts are being treated at the recommended Phase 2 dose of 600 mg. Results: At data-cutoff, 50 pts (46% checkpoint-experienced) were treated in Dose Escalation, and 157 pts (32% checkpoint-experienced) in Cohort Expansion. No MTD was defined. Treatment-related adverse events (TRAEs) occurred in 146/207 (70.5%) pts, most commonly fatigue (19%) and nausea (11%). The rate of Grade ≥ 3 TRAEs was 23.2%. Immune-related AEs were consistent with events observed with anti-PD-1 antibodies. Mean half-life was 11 days; peripheral blood flow cytometry analyses confirmed full and sustained on-target binding during treatment at doses ≥ 120 mg. Among 41 response-evaluable [RE] dose escalation pts, 3 confirmed partial responses [cPRs] (triple negative breast cancer [TNBC], mesothelioma, gastric cancer) per RECIST 1.1 were observed, while 21 pts had stable disease [SD]. Among select expansion cohorts, PRs have been observed in epithelial ovarian cancer (n=2; both cPRs, and 7 with SD among 15 RE pts) and TNBC (n=2; 1 cPR, 1 unconfirmed PR [uPR], and 5 with SD among 14 RE pts). In a cohort of pts with HER2+ tumors treated with MGD013 in combination with margetuximab (investigational anti-HER-2 antibody), 3 PRs have been observed (breast [n=2], colorectal [n=1]; 1 cPR, 2 uPRs) and 2 pts with SD among 6 RE pts. Objective responses have been observed in several pts after prior anti-PD-1 therapy. Investigations into potential correlative biomarkers including LAG-3 and PD-1 are ongoing. Conclusions: MGD013, a novel molecule designed to coordinately block PD-1 and LAG-3, has demonstrated an acceptable safety profile and encouraging early evidence of anti-tumor activity. Clinical trial information: NCT03219268 .