bluuebunny/crossref_metadata_2025 huggingface dataset:
Updated predictive analysis of the WHO-defined molecular subgroups of low-grade gliomas within the high-risk treatment arms of NRG Oncology/RTOG 9802.
Authors: Bell Erica Hlavin , Won Minhee , Fleming Jessica L. , Becker Aline P. , McElroy Joseph P. , Shaw Edward G. , Mehta Minesh P. , Brachman David G. , Gertler Stanley Z. , Murtha Albert D. , Schultz Christopher J. , Johnson David B. , Laack Nadia N. , Hunter Grant Kirton , Crocker Ian R. , Chakravarti Arnab
Published: May 2019

2002

Background: This study sought to update the predictive significance of the three WHO-defined molecular glioma subgroups ( IDHwt, IDHmt/noncodel, and IDHmt/codel) in the subset of specimens available for analysis in NRG Oncology/RTOG 9802, a phase III trial of high-risk low-grade gliomas (LGGs) treated with radiation (RT) with and without PCV after biopsy/surgical resection. Notably, this is the first phase III study to evaluate the predictive value of the WHO subgroups in LGGs using prospectively-collected, well-annotated long-term overall survival data, in a post-hoc analysis. Methods: IDH1/2 mutation status was determined by immunohistochemistry and/or next-generation sequencing. 1p/19q status was determined by Oncoscan and/or 450K methylation data. Treatment effects on overall survival (OS) and progression-free survival (PFS) by marker status were determined by the Cox proportional hazard model and tested using the log-rank test in a secondary and exploratory analysis. Results: Of all the randomized eligible high-risk G2 patients (N = 251) in NRG Oncology/RTOG 9802, 106(42%) patients had tissue available with sufficient quality DNA for profiling. Of these, 80(75%) were IDHmut; 43(41%) were IDHmut/non-co-deleted, 37(35%) were IDHmut/co-deleted, and 26(24%) were IDHwt. Upon univariate analyses, no significant difference in either PFS or OS was observed with the addition of PCV in the IDHwt subgroup. Both the IDHmut/non-co-deleted and IDHmut/co-deleted subgroups were significantly correlated with longer PFS (HR = 0.32; p = 0.003; HR = 0.13; p < 0.001) and OS (HR = 0.38; p = 0.013; HR = 0.21; p = 0.029) in the RT plus PCV arm, respectively. Conclusions: Our analyses suggest that both IDHmut/non-co-deleted and IDHmut/co-deleted subgroups received benefit from treatment with PCV although sample size is limited and analyses are post-hoc. Our results also support the notion that IDHwt high-risk LGG patients do not benefit from the addition of PCV to RT. Funding: U10CA180868, U10CA180822, and U24CA196067. Also, R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01, BTFC, OSU-CCC (all to AC). Clinical trial information: NCT00003375.
Efficacy and safety of selinexor in recurrent glioblastoma.
Authors: Lassman Andrew B. , Wen Patrick Y. , Van Den Bent Martin J. , Plotkin Scott Randall , Walenkamp Anna Maria Elisabeth , Huang Xiu , Rodriguez-Lopez Karla , Kauffman Michael G. , Shacham Sharon , Mau-Sørensen Morten
Published: May 2019

2005

Background: New treatment modalities are needed for recurrent glioblastoma (rGBM). Selinexor (SEL) is a novel, oral selective inhibitor of nuclear export which forces nuclear retention of tumor suppressor proteins including p53 and p27, leading to apoptosis. We previously reported interim results showing tolerability, preliminary efficacy, and blood-brain barrier penetration in a surgical cohort (N = 8). We now report updated results following completion of accrual to non-surgical cohorts (N = 68). Methods: This is an open-label, multicenter, phase 2 study of SEL monotherapy. Patients (pts) not undergoing surgery for measurable rGBM (per RANO) were enrolled in one of 3 arms encompassing different dosing schedules. Treatment was continuous, although cycles were defined as 28 days and response was assessed every other cycle by MRI. Prior treatment with radiotherapy and temozolomide was required and prior bevacizumab was exclusionary. The primary endpoint was 6-month progression free survival (6mPFS) rate, calculated by the Kaplan Meier method. Results: A total of 76 pts were enrolled. Median age was 56 years (range 21-78). Median number of prior treatments was 2 (range 1-7). At the end of the 6 cycles, 30.2% patients on 80 mg QW were free from progression. The 6mPFS rate on 80 mg QW was 15.1%. Best RANO-defined responses (assessed locally) among 26 evaluable pts on 80 mg QW included 1 complete response, 2 partial responses, 7 stable disease, and 16 with progressive disease. Median duration of response was 10.8 months. The most common related adverse events in pts on ~85 mg BIW/60 mg BIW/80 mg QW were nausea (42%/64%/60%), leukopenia (38%/7%/43%), fatigue (71%/71%/43%), neutropenia (29%/14%/33%), decreased appetite (46%/71%/27%), and thrombocytopenia (67%/29%/23%). Conclusions: SEL demonstrated efficacy, with durable responses and disease stabilization in rGBM. Based on the favorable efficacy and safety profile, SEL at a dose of 80 mg QW is recommended for further development in rGBM. Clinical trial information: NCT01986348. [Table: see text]
Activity of larotrectinib in TRK fusion cancer patients with brain metastases or primary central nervous system tumors.
Authors: Drilon Alexander E. , DuBois Steven G. , Farago Anna F. , Geoerger Birgit , Grilley-Olson Juneko E. , Hong David S. , Sohal Davendra , van Tilburg Cornelis Martinus , Ziegler David Simon , Ku Nora , Cox Michael Craig , Nanda Shivani , Childs Barrett H. , Doz Francois P.
Published: May 2019

2006

Background: TRK fusions are oncogenic drivers of a variety of cancers, many of which can involve the central nervous system (CNS). Larotrectinib is an FDA-approved selective TRK inhibitor for the treatment of TRK fusion cancer (Drilon et al, NEJM 2018). While larotrectinib has been shown to cross the blood–brain barrier (Ziegler et al, Br J Cancer 2018), its clinical activity in a series of TRK fusion cancers with primary or metastatic intracranial disease has not been described. Methods: Patients (pts) with non-primary CNS solid tumors with brain metastases, or primary CNS tumors harboring a TRK fusion treated with larotrectinib in 2 clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression (PD), withdrawal, or unacceptable toxicity. Disease status was investigator-assessed (RANO and RECIST). Data cutoff: July 30, 2018. Results: 14 pts were identified: 5 non-primary CNS solid tumors (3 lung cancer, 2 thyroid cancer; fusion type: 2 ETV6-NTRK3, 2 SQSTM1-NTRK3, 1 EPS15-NTRK1; age range 25–79 y) and 9 primary CNS tumors (3 glioma, 2 glioblastoma, 1 astrocytoma, 3 NOS; fusion type: 3 BCR-NTRK2, 2 KANK-NTRK2, 1 each of AFAP1-NTRK1, AGTPBP1-NTRK2, ETV6-NTRK3, SPECC1L-NTRK2; age range 2–79 y). In the 5 pts with non-primary CNS tumors, the best objective response to therapy was PR in 3 (60%, 1 pending confirmation), SD in 1 (20%), and not evaluable (NE) in 1 (20%). Duration of response ranged from 9+ to 13 mo. In the 9 pts with primary CNS tumors, disease control was achieved in all evaluable pts (primary PD not observed; 1 pt required dose increase). The best objective response to therapy was PR in 1 (11%; pending confirmation, −55% tumor shrinkage, ongoing at 3.7 mo), SD in 7 (78%; tumor shrinkage range −1% to −24% for pts with measurable disease, 5 had SD > 4 mo), and NE in 1 (11%). Duration of treatment ranged from 2.8–9.2+ mo. Conclusions: Larotrectinib is active in pts with TRK fusion cancers with intracranial disease. Confirmed responses and durable disease control were seen in metastatic disease and primary CNS tumors of various histologies. These results further support expanded testing for TRK fusions across all cancers, including primary CNS tumors. Clinical trial information: NCT02637687 and NCT02576431.
Impact of predictive impact of MGMT promoter methylation in malignant astrocytomas depends on the methylation subgroup.
Authors: Wick Wolfgang , Kessler Tobias , Platten Michael , Meisner Christoph , Bamberg Michael , Herrlinger Ulrich , Happold Caroline , Weisang Sarah , Boelting Hanna , Steinbach Joachim , Reifenberger Guido , Sahm Felix , von Deimling Andreas , Wick Antje , Weller Michael
Published: May 2019

2013

Background: O6-methylguanine DNA-methyl transferase (MGMT) status is predictive for alkylating chemotherapy in most series, but there are non-benefitting subgroups. Despite multiple attempts, MGMT has not been unambiguously established as a predictive biomarker for patients with malignant gliomas. Further, these tumors are to be better classified according to global methylation profiles. Methods: Long-term efficacy data of the NOA-08 trial (NCT01502241) that compared efficacy and safety of radiotherapy (RT, n= 176) to temozolomide (TMZ, n= 193) in patients > 65 years with anaplastic astrocytoma (AA) or GB as well as genome-wide DNA methylation patterns and copy number variations assessed by methylation arrays in a biomarker subset ( n= 104) and an independent cohort ( n= 380) have been used to assess the interaction between MGMT status and methylation subgroups. Results: In the long-term update of NOA-08 patients with MGMT methylated tumors had longer OS and EFS when treated with TMZ (18.4 [13.9-24.4] months and 8.5 [6.9-13.3] months) versus RT (9.6 [6.4-13.7] months and 4.8 [4.3-6.2] months, HR 0.44 [0.27-0.70], p < 0.001 for OS and 0.46 [0.29-0.73], p = 0.001 for EFS). These data compared favorably with recently published data from patients treated with chemoradiation (Perry et al. NEJM 2017). Importantly, only patients with glioblastomas of the methylation class receptor tyrosine kinase II (RTKII) and mesenchymal but not RTK I demonstrated the predictive impact of MGMT in the NOA and the independent validation cohort. Conclusions: MGMT promoter methylation as a strong but methylation subclass-dependent predictive biomarker for the use of alkylating chemotherapy in malignant gliomas. The data call for embedding of MGMT tests into global methylation analyses for all patients with malignant gliomas potentially treated with alkylating chemotherapy.
Genomic characterization of lung tumors and metastatic (Met) sites in advanced (Adv) NSCLC.
Authors: Willard Melinda D , Nash Smyth Emily Nash , Tiu Ramon Velasquez , Beyrer Julie , Zhu Yajun Emily , Bowman Lee , Sheffield Kristin M , Han Yimei , Brastianos Priscilla
Published: May 2019

2014

Background: Molecular alterations (MA) found in brain (Br) mets of NSCLC pts can differ from primary and/or other met sites, which may explain why therapies targeting primary tumors are less effective at preventing and treating intracranial disease. We analyzed the frequency of known driver genes in adv NSCLC pts and the association with overall survival (OS). Methods: This retrospective observational study identified pts from the Flatiron- Foundation Medicine NSCLC Clinico-Genomic Database who were diagnosed with adv NSCLC from 1 Jan 2011 to 31 Oct 2017 and had tumor tissue analyzed at any time following initial diagnosis via targeted DNA sequencing by FoundationOne. Descriptive statistics summarized MA from lung and met sites (Br and non-brain [NB]). OS was measured from adv diagnosis to death or last activity date (censored). Multivariable Cox proportional hazard regression model was used for time-to-event analysis. Results: Of 3257 pts, data were available from lung (n = 1621), Br (n = 180), and NB sites (n = 377): liver (n = 167), bone (n = 124), adrenal (n = 63), and spine (n = 23). Median age at adv diagnosis was 66.2 yrs. TP53(63.3%), KRAS(28.8%), EGFR(15.6%), STK11 (13.5%), and CDKN2A(8.5%) were frequently mutated genes in lung samples. Genes for Br vs NB sites included TP53(70.6%; 64.7%), KRAS(36.1%; 26.5%), EGFR (9.4%; 18.8%), STK11 (18.9%; 12.7%), and CDKN2A(6.1%; 10.1). KEAP1alterations were also present in 10% (Br), 7.4% (NB), and 6% of lung samples. In treated pts, lack of alterations in select genes ( STK11, TP53, KEAP1) was associated with longer OS, whereas lack of other alterations ( ARID1A, EGFR, ALK, ROS1) was associated with a shorter OS (p < 0.05). Patients with select mutations co-occurring with KRAS had higher risk of death compared to those with KRAS only (p < 0.05). Conclusions: Based on pts with NSCLC whose tumor tissue underwent DNA sequencing, the most frequently altered genes in lung and Br samples included TP53, KRAS, EGFR, STK11, and CDKN2A, with some being significantly associated with OS. Prognosis of NSCLC pts depends on clinical, demographic, and genomic factors and should be carefully considered to optimize clinical outcome.
Barriers to accrual and enrollment in brain tumor trials.
Authors: Lee Eudocia Quant , Chukwueke Ugonma Nnenna , Hervey-Jumper Shawn L. , De Groot John Frederick , Leone Jose Pablo , Armstrong Terri S. , Chang Susan Marina , Arons David , Oliver Kathy Rose , Galanis Evanthia , Friday Bret Edward Buckley , Lin Nancy U. , Mehta Minesh P. , Penas-Prado Marta , Vogelbaum Michael A. , Sahebjam Solmaz , Van Den Bent Martin J. , Weller Michael , Reardon David A. , Wen Patrick Y.
Published: May 2019

2024

Background: A major impediment to improving neuro-oncology outcomes is poor clinical trial accrual. Methods: We convened a multi-stakeholder group including Society for Neuro-Oncology, Response Assessment in Neuro-Oncology, patient advocacy groups, clinical trial cooperative groups, and other partners to determine how we can improve trial accrual. Results: We describe selected factors contributing to poor trial accrual and possible solutions. Conclusions: We will implement strategies with the intent to double trial accrual over the next 5 years. [Table: see text]
Phase 1/2a study of once daily oral BAL101553, a novel tumor checkpoint controller (TCC), in adult patients with progressive or recurrent glioblastoma (GBM) or high-grade glioma.
Authors: Lopez Juanita Suzanne , Kristeleit Rebecca Sophie , Rulach Robert , Haris Noor Md , Scaranti Mariana , Mulholland Paul James , Crawford Donna , Bashir Saira , Aversa Caterina , Hannah Alison L. , Anderson Stephanie , Engelhardt Marc , Kaindl Thomas , Larger Patrice , McKernan Phil , Evans TR Jeffry , Plummer Elizabeth
Published: May 2019

2025

Background: BAL101553 (prodrug of BAL27862) is a novel TCC that promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 is a lipophilic, small molecule shown in rodents to penetrate the brain (brain/plasma ratio around unity), with promising antitumor activity in orthotopic preclinical GBM models as monotherapy or in combination with radiotherapy (RT) with or without temozolomide. In this ongoing study (NCT02490800, CDI-CS-002), daily oral BAL101553 was initially examined in solid-tumor patients, with an MTD of 16 mg/d and DLTs of G4 hyponatremia and G2 hallucinations (Lopez 2018, JCO 36, 2018, suppl. A2530). Subsequently the study was expanded by including a separate cohort of patients with progressive or recurrent GBM or high-grade glioma (Ingles Garces 2017, JCO 35, 2018, suppl. TPS2601). Methods: Patients with histologically-confirmed GBM or high-grade glioma, with progressive or recurrent disease after prior RT with/without chemotherapy, received once-daily oral BAL101553 (28-day cycles) in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD). Adverse events were assessed by CTCAE v4.03 grade (G), and tumor response by RANO every two cycles. Pharmacokinetics (PK) were evaluated on Day 1 of Cycles 1 and 2. Results: In the ongoing study, 23 pts (13M/10F; median age 50 y), median (min–max) number of prior regimens = 2 (1–5), received doses of 8, 15, 20, 25 or 30 mg oral BAL101553 once daily. One DLT of reversible G2 depression and fatigue occurred at 20 mg. Both mean Cmax and AUC increased with dose between 8 and 30 mg. The PK exposure in GBM patients was lower than for solid tumor patients, in particular at 20 and 25 mg. At 25 mg/d (n = 3), one patient with IDH-mutated GBM had a partial response (63% area reduction per RANO) and continues on study > 8 months, and another patient had stable disease for 5 months. At 15–20 mg/d, stable disease was observed in 3/10 patients. Conclusions: The current data in patients with GBM or high-grade glioma suggest that BAL101553 is well tolerated at dose levels above the MTD established in patients with advanced solid tumors, and shows indications of clinical activity. Clinical trial information: 02490800.
GLIAVAX: A stratified phase II clinical trial of avelumab and axitinib in patients with recurrent glioblastoma.
Authors: Neyns Bart , Ben Salama Laila , Awada Gil , De Cremer Jennifer , Schwarze Julia Katharina , Seynaeve Laura , Du Four Stephanie , Fischbuch Lydia , Vanbinst Anne-Marie , Everaert Hendrik , Michotte Alex , Rogiers Anne , Theuns Peter , Duerinck Johnny
Published: May 2019

2034

Background: Patients (pts) with recurrent glioblastoma (rGB) have a poor prognosis, and no treatment option demonstrated to improve survival in a randomized trial. Axitinib (AXI), an oral VEGFR 1-3 inhibitor has demonstrated single agent activity in rGB and reduces the need for corticosteroids (CS). Avelumab (AVE) is a fully human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types. Combination of AXI and AVE may improve the outcome of pts with rGB. Methods: This open-label, dual-strata, single-center phase 2 clinical trial investigated the activity of AXI plus AVE in adult pts with rGB following prior surgery, RT and temozolomide. Pts were stratified according to their baseline use of CS. Pts without baseline need for CS initiated treatment with AXI (5 mg oral BID) plus AVE (10 mg/kg IV Q2W) (cohort-1). Pts in need of CS initiated AXI as a monotherapy; AVE could be added to AXI after 6 wks if the CS dose could be tapered to a physiologic dose level or less (cohort-2). Six-month-PFS served as the primary endpoint (with a prespecified threshold of ≥ 50% for cohort-1) according to Fleming one-stage design. Results: Between Jun 2017 and Aug 2018, 54 pts (27 per cohort) were enrolled (med age 55 y [range 19-75]; 63% male; 91% WHO PS 0-1). All pts in cohort-1 and 16 pts (59%) in cohort-2 received at least 1 dose of AVE. The 6-month-PFS was 18% (95% CI 4-33) in both cohorts. At the time of analysis, 2 pts were progression-free and continuing study treatment. Median OS in cohort-1 and -2 was respectively 26 wks (95% CI 21-32) and 18 wks (95% CI 14-22). No clear relation was found between baseline cognitive functioning (Cogstate subtests) and PFS/OS. The best overall response rate (iRANO) was 41% and 26% respectively for pts in cohort-1 and -2. The most frequent all-grade treatment-related adverse events (TRAE) were dysphonia (67%), lymphopenia (50%), diarrhea (48%), hypertension (48%), and fatigue (46%). The incidence of grade 3-4 TRAE was 30%; there were no grade 5 AE. Conclusions: The combination of AVE plus AXI is sufficiently well tolerated but did not meet the threshold for activity justifying further investigation in an unselected population of patients with rGB. Clinical trial information: NCT03291314.
Effect of grade on survival in IDH-mutant grade II and grade III gliomas.
Authors: Lamberti Giuseppe , Franceschi Enrico , Tosoni Alicia , Mura Antonella , Paccapelo Alexandro , Foschini Maria Pia , Asioli Sofia , De Biase Dario , Pession Annalisa , Tallini Giovanni , Bartolini Stefania , Giangaspero Felice , Brandes Alba Ariela
Published: May 2019

2036

Background: The 2016 WHO classification dramatically changed the diagnosis of gliomas. Diffuse gliomas are classified according to the presence of IDH-mutation (IDH-mut) and the deletion of both 1p and 19q chromosome arms (1p/19q codel). Now debate is whether grade still has an independent prognostic value. The aim of this study was to find out if grade is a prognostic factor independently of molecular status. Methods: We analyzed our institutional data warehouse for all consecutive patients (pts) with newly diagnosed, histologically proven Grade II or Grade III IDH-mut gliomas. IDH 1/2 assessment by polymerase chain reaction (PCR)or immunohistochemistry (IHC) was accepted. Next Generation Sequencing (NGS) for IDH1(exon 4) and IDH2(exon 4) was performed on all specimens wild-type for the IDH. Results: The analysis included all the 399 pts who had a grade II (n = 250, 62.7%) or grade III (n = 149, 37.3%). Median follow-up time was 105.3 months. After surgery, 72 pts (18.0%) received RT alone, 44 (11.0%) received CT alone, 135 (33.8%) received both RT and CT, and 142 (35.6%) follow-up without any treatment. Median survival was 148.1 months. In multivariate analysis Grade (HR = 0.342, 95%CI: 0.221 – 0.531; P < 0.001) and 1p/19q codeletion (HR = 0.440, 95%CI: 0.290 – 0.668; P < 0.001) were independently associated with a lower risk for death. The difference in survival remained when adjusted for histological subtype. Residual disease after surgery or biopsy negatively affected survival (HR 2.151, 95%CI 1.375 – 3.367, P = 0.001). Post-surgical treatment with RT + adjuvant CT improves survival in respect to follow-up and other treatments (HR: 0.316, 95%CI 0.156 – 0.641, P = 0.001). Conclusions: Grade still affects survival in IDH mutant Grade II and III gliomas. This effect was independent onmolecular features, surgical extension and post-surgical treatments. Clinical management of gliomas should continue to take into account grade as well as molecular characteristics.
Adjuvant chemotherapy to improve survival in average-risk adult medulloblastoma patients: Long-term results.
Authors: Lamberti Giuseppe , Franceschi Enrico , Tosoni Alicia , Minichillo Santino , Di Battista Monica , Paccapelo Alexandro , Sturiale Carmelo , Mascarin Maurizio , Masotto Barbara , Volpin Lorenzo , Bartolini Stefania , Giangaspero Felice , Brandes Alba Ariela
Published: May 2019

2037

Background: Medulloblastoma is extremely rare in adults and, therefore, it is difficult to accrual patients in clinical trials. Radical surgery and radiotherapy (RT) provide a significant control of disease. Nevertheless, about 25% of average-risk patients have a relapse and die because of disease progression. The role of chemotherapy (CT) after standard RT for average-risk adult patients remains controversial. Methods: We analyzed 48 average-risk patients according to Chang classification diagnosed from 1988 to 2016. Median age was 29 years (range 16-61), M/F ratio was 26 (54.2%)/22 (45.8%). Fifteen patients had classic medulloblastoma (31.3%), 15 patients had desmoplastic medulloblastoma (31.3%), 5 patients had extensive nodularity (10.4%) and 2 patients had large cells/anaplastic histology (4.2%). The patients were homogeneously distributed in the two groups: 24 (50%) received adjuvant RT alone and 24 (50%) received RT + CT that consisted in a platinum-etoposide based combination. Results: After a median follow-up of 12.5 years, CT increases progression-free survival rate at 15 years (PFS-15 82.3 ± 8.0% in RT-CT group vs. 38.5% ± 13.0% in RT group p = 0.05) and overall survival rate at 15 years (OS-15 89.3% 7.2% vs. 52.0% 13.1%, p = 0.02). Among patients receiving CT, the reported grade ≥ 3 adverse events were: 9 cases of neutropenia; 6 cases of G3 neutropenia (25%) and 3 cases of G4 neutropenia (13%), 1 case of G3 thrombocytopenia (4%) and 2 cases of G3 nausea (8%). Conclusions: Our study with a long follow up period suggests that adding adjuvant chemotherapy to RT might improve PFS and OS in average-risk adult medulloblastoma patients.
A gene signature of response to radiotherapy in patients with grade II-III oligodendrogliomas.
Authors: Moyal Elizabeth , Gilhodes Julia , Peyraga Guillaume , Uro-Coste Emmanuelle , Pouessel Damien , Larrieu-Ciron Delphine , Carpentier Catherine , Ducray Francois , Dehais Caroline ,   POLA Network
Published: May 2019

2041

Background: Grade II and III Oligodendroglioma associate mutations of isocitrate deshydrogenase 1 or 2 genes and the whole-arm chromosomal loss of 1p and 19q and have a better prognosis than other gliomas. However, even if the preferred treatment consists of a combination of radiotherapy (RT) and chemotherapy, some patients will less respond to this treatment and will relapse faster , in part because of an heterogeneity in the response to RT. In the aim to identify factors of response to RT, we analyzed clinical and molecular data of patients with grade II-III oligodendroglioma exclusively treated with RT in the POLA cohort. Methods: Gene expression profiles on Affymetrix expression arrays of patients from the POLA cohort with co-deleted 1p/19q grade II/II gliomas treated by exclusive RT were used to identify a gene expression set predictive of radiation sensitivity. The primary endpoint was the progression free survival (PFS), defined as the time from treatment start until progression or death. A supervised approach with penalized regression was applied to select most informative predictors, and then a risk score was created based on the linear predictor given by the multivariable model. Results: Forty-five patients corresponded to the study criteria, with a median age at diagnosis of 45 (range 23- 64). The supervised approach allowed identifying a three-gene prognostic set including Semaphorin -3C (SEMA3C), Neuronal Pentraxin 2 (NPTX2 ) and the Metabotropic Glutamate Receptor 5 (GRM5), involved in proliferation, migration and inflammation. The risk score associated to these three genes was statistically associated to PFS (HR = 2.72, p = 0.00005) and remains significant when adjusted on clinical covariates age at diagnosis, necrosis, endothelial proliferation and type of surgery (complete, partial or subtotal surgery) (HRadj = 2.36, p = 0.001). Conclusions: We report an independent three genes SEMA3C-NPTX2-GRM5 risk score signature of response to radiotherapy in patients with oligodendroglioma, which highlights the heterogeneous response in this reputed good prognosis population. This signature could help in determining the adapted treatment as well as potential new targets to address.
A preliminary comprehensive molecular-based nomogram for individualized estimation of survival in patients with newly diagnosed glioblastoma utilizing global microRNA expression data.
Authors: Fabian Denise , Bell Erica Hlavin , McElroy Joseph P. , Cui Tiantian , Fleming Jessica L. , Becker Aline P. , Geurts Marjolein , Haque Jahar , Robe Pierre A. , Chakravarti Arnab
Published: May 2019

2044

Background: Glioblastoma (GBM) is the most aggressive and common primary brain tumor. Nomograms are prediction models that help form individualized risk scores for cancer patients, which are valuable for treatment decision-making. The aim of this study is to create a refined nomogram by including novel molecular variables beyond MGMT promoter methylation. Methods: Clinical data and miRNA expression data were obtained from 226 newly diagnosed GBM patients. Clinical data included age at diagnosis, sex, Karnofsky performance status (KPS), extent of resection, O6-methylguanine-DNA methyltransferase ( MGMT) promoter methylation status, IDH mutation status and overall survival. Due to low representation of less than 13 cases each, IDH mutant glioblastomas and patients submitted to biopsy-only were excluded. Total RNA was isolated from formalin-fixed paraffin-embedded (FFPE) tissues; miRNA expression was subsequently measured using the NanoString human miRNA v3a assay. A Cox regression model was developed using glmnet R package with the elastic net penalty while adjusting for known prognostic factors. A dichotomized genomic score was created by finding the optimal cutpoint (maximum association with survival) of the linear combination of the selected. A nomogram was generated using known clinical prognostic factors, specifically age, sex, KPS, and MGMT status along with the dichotomized genomic score. Results: Four novel miRNAs were found to significantly correlate with overall survival and were used to create the dichotomized miRNA genomic score (GS). This score split the cohort into a poor performing group (GS_high) and a better performing group (GS_low) (p = 0.0031). A final nomogram was created using the Cox proportional hazards model (Figure 1). Factors that correlated with improved survival included younger age, KPS > 70, MGMT methylation and a low genomic score. Conclusions: This study is a proof of concept demonstrating that integration of molecular variables beyond MGMT methylation improve existing nomograms to provide individualized information about patient prognosis. Future directions include a more comprehensive analysis, including proteomic and methylation data, and subsequent validation in an external cohort. Finally, network analysis integrating molecular signatures of poor performers will help identify therapeutic targets.
Clinical efficacy of tumor-treating fields for newly diagnosed glioblastoma.
Authors: Liu Yang , Richardson Margie , Warren Kwanza , Strawderman Myla S. , Mohile Nimish , Milano Michael T. , Walter Kevin
Published: May 2019

2046

Background: Recent clinical trials have shown that adding tumor treating fields (TTF) to the Stupp protocol (SP) has increased survival after glioblastoma (GBM) diagnosis. However, whether this regimen improves population-based survival for patients with GBM remains unknown. Methods: We retrospectively identified adult patients with newly diagnosed GBM treated at our institution from January 2000 to July 2017 (n = 438, median age: 63 years).We grouped patients into three time periods for comparison: 2000-2004 (group 1, prior to SP), 2005-2013 (group 2, SP) and 2014-2017 (group 3, adding TTF to SP). The Kaplan-Meier method was used to estimate survival. Statistical analysis included unadjusted group comparisons by Chi-square and Log-rank tests and adjusted group comparisons using logistic and Cox models. Results: Thirty-seven percent (43/117) of patients with GBM in group 3 received TTF with SP therapy; when compared to those who received SP only, these patients had significant improvements in 6-month and 1-year overall survival (OS) rates (100.0% vs. 82.4%, p < 0.01; 86.0% vs. 66.2%, p < 0.05, respectively) (unadjusted for prognostic factors including sex, age, KPS and extent of resection) and an increased trend of median OS (479.0 vs. 448 days, p = 0.269). However, after adjusting for those prognostic factors, we didn’t find a statistically better survival for patients treated with TTF (OR: 6.156, p = 0.097, OR: 2.102, p = 0.185, respectively). Furthermore, multivariate Cox proportion hazards model after adjusting for those prognostic factors showed no significant survival benefits for patients treated with TTF and SP compared to those treated with SP only (HR = 0.797, p = 0.648). In addition, we didn’t find significant increases of 6-month, 1-year survival rates and median OS for patients in group 3 when compared to those in group 2 who had seen increased trends of survival trends when compared to those in group 1. Conclusions: Although adding TTF to SP appeared to benefit patients with GBM, this effect might be due to selection bias, e.g., TTF was offered to those patients with better prognostic factors. Ascertaining the long-term benefits of TTF requires further investigation.
Evaluating the capacity of connectome analysis to predict survival in high-grade astrocytoma.
Authors: Harrison Rebecca A. , Liu Rongjie , Rao Vikram , Petersen Melissa , Dyson Hannah , Weathers Shiao-Pei S. , Alfaro-Munoz Kristin , De Groot John Frederick , Kesler Shelli
Published: May 2019

2049

Background: While factors such as age, histology and tumor molecular variants (e.g. IDH status) contribute to prognosis in patients with high grade astrocytoma (HGA), there remains a wide variability in patient survival outcomes. The connectome, or brain network organization, incorporates biologic, molecular and environmental processes providing a uniquely parsimonious summary of key prognostic factors. This study compared the capacity of machine learning (ML) models based on baseline connectomics and clinical variables to predict patient survival in HGA. Methods: Patients with a new diagnosis of HGA and a presurgical 3D, T1-weighted MRI available were retrospectively identified. Individual patient connectomes were derived from MRI with 90 cortical/subcortical features. Presurgical clinical features included age, gender, histology, tumor grade and IDH status. Three ML algorithms were implemented: extreme learning machine with Buckley–James estimator (ELMBJ), random survival forest (RSF) with logrank splitting and RSF with concordance index (CI) splitting. For each algorithm, we used a 60/40 training/testing split with 50 iterations and CI as the performance metric. We tested three models: 1) connectome only, 2) clinical only, and 3) connectome plus clinical variables. Results: Of patients identified (n = 105), 66 had glioblastoma and 39 had anaplastic astrocytoma. Thirty-eight harbored IDH mutation. Median overall survival was 27.43 months (SD 39.57). Connectome-only models showed better prediction performance compared to clinical-only models across all algorithms. ELMBJ showed the best performance (connectome median CI = 0.522, clinical CI = 0.201). Connectome models also performed as well as combined models (e.g. median CI = 0.523 for ELMBJ). Conclusions: This study demonstrates the potential of a connectome model to predict survival of patients with HGA. Replication in a larger sample is required to validate these results and refine ML models including examination of additional clinical features. If successful, use of a simple T1 MRI could provide additional variables to augment existing prognostic prediction, especially in scenarios where tumor genotyping is not available.
Decision making in surveillance of high-grade gliomas using perfusion MRI as adjunct to conventional MRI and artificial intelligence.
Authors: Bisdas Sotirios , Shakallis Loizos , McEvoy Andy , Miserocchi Anna , Samandouras George , Brandner Sebastian , Rees Jeremy , Ferscht Naomi , Cardoso Jorge M , Panovska-Griffiths Jasmina , Sudre Carole , Shaikh Faiq , Roettger Diana
Published: May 2019

2054

Background: Surveillance of High-Grade Gliomas (HGGs) remains a major challenge in clinical neurooncology. Histopathological validation is not an option during the course of disease and imaging surveillance suffers from ambiguous features of both disease progression and treatment related changes. This study aimed to differentiate between Pseudoprogression (PsP) and Progressive Disease (PD) using an artificial intelligence (support vector machine - SVM) classification algorithm. Methods: Two groups of patients with histologically proven HGGs were analysed, a group with a single time point DSC perfusion MRI (45 patients) and a group with multiple time point DSC perfusion MRI (19 patients). Both groups included conventional MRI studies prior and after each perfusion MRI. This study design aimed to replicate decision making in clinical practice including multiple previous studies for each patient. SVM training was performed with all available MRI studies for each group and classification was based on different feature datasets from a single or multiple (subtracted features) time points. Classification accuracy comparisons were performed by calculating prediction error rates for different feature datasets and different time point analyses. Results: Our results indicate that the addition of multiple time point perfusion MRI combined with structural (conventional with gadolinium-enhanced sequences) MRI features results in optimal classification performance (median error rate: 0.016, lowest value dispersion). Subtracted feature datasets improved classification performance, more prominently when the final and first perfusion studies were included in the analysis. On the contrary, in the single time point group analysis, structural feature-based classification performed best (median error rate: 0.012). Conclusions: Validation of our results with a larger patient cohort may have significant clinical importance in optimising imaging surveillance and clinical decision making for patients with HGG.
Molecular genetic, host-derived and clinical determinants of long-term survival in glioblastoma: First results from the ETERNITY study (EORTC 1419).
Authors: Weller Michael , Reifenberger Guido , Le Rhun Emilie , Clarke Jennifer Leigh , Soffietti Riccardo , Wick Antje , Chinot Olivier L. , Ducray Francois , Hau Peter , McDonald Kerrie Leanne , Marosi Christine , Schnell Oliver , Hottinger Andreas Felix , Reijneveld Jaap C. , Lombardi Giuseppe , Wen Patrick Y. , Klein Martin , Gorlia Thierry , Felsberg Joerg , Hertler Caroline ,   for the BTFC Consortium on Long-term Survival with Glioblastoma & the EORTC Brain Tumor Group
Published: May 2019

2056

Background: Glioblastoma represents the most aggressive primary brain tumor in adults, and less than 5% of patients survive 5 years from diagnosis. Factors influencing this long-term survival are poorly understood. Methods: In cooperation with the European Organisation for Research and Treatment of Cancer (EORTC) in Brussels, Belgium, more than 20 clinical sites in the US, Europe and Australia have registered patients with centrally confirmed glioblastoma who survived ≥ 5 years, collecting clinical data including therapy and quality of life-related factors, as well as biospecimens allowing to analyse molecular and immunological parameters. Results: At the cut-off of December 31, 2018, 392 patients were registered, of which 232 had glioblastoma confirmed by central pathology review; 59 dropped out due to histology other than glioblastoma. Glioblastomas were isocitrate dehydrogenase (IDH)-wildtype in 70.7% and had a positive O6-methylguanine DNA methyltransferase (MGMT) promotor methylation status in 75.9%. Median age at diagnosis was 52 years (range: 21-77 years). There was enrichment for patients with gross total resection. Further analyses are ongoing. Conclusions: In a comprehensive effort, the consortium funded by the US Brain Tumor Funders’ Collaborative characterizes factors modulating long-term survival in glioblastoma in a unique large patient cohort. Clinical trial information: NCT 03770468.
Oncolytic polio/rhinovirus recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG): Experience with retreatment of survivors from the phase I trial.
Authors: Desjardins Annick , Gromeier Matthias , Herndon James Emmett , Randazzo Dina , Threatt Stevie , Lipp Eric S. , Miller Elizabeth S. , Jackman Jennifer , Bolognesi Dani P. , Friedman Allan H. , Friedman Henry S. , McSherry Frances , Peters Katherine B. , Johnson Margaret O , Sampson John H. , Ashley David M. , Bigner Darell D.
Published: May 2019

2060

Background: We completed a study evaluating a single intratumoral delivery of PVSRIPO in recurrent WHO grade IV MG patients (N Engl J Med. 2018 Jul 12;379(2):150-161). Some patients who originally benefitted from the infusion of PVSRIPO demonstrated tumor recurrence, and we hypothesized that retreatment could trigger an immune recall effect, further extending their survival. We now report the impact of second and third intratumoral reinfusion of PVSRIPO in patients treated in the original dose finding study. Methods: Eligible patients were adults with recurrent supratentorial WHO grade IV MG who were experiencing disease recurrence after having benefitted from the first infusion of PVSRIPO. Additional eligibility criteria included: solitary tumor 1-5.5cm in diameter; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; KPS≥70%; and positive anti-polio titer. One patient each was retreated at 1 x 107 TCID50 and 1 x 1010 TCID50, and three patients were retreated on the identified phase 2 dose of 5 x 107 TCID50. Results: As of 2/09/2019, five patients have received a second intratumoral dose of PVSRIPO on study, one of which received a total of 3 doses. The patients who received two infusions of PVSRIPO were retreated 72 months, 43 months, 34 months, and 6 months after the first infusion. One additional patient received a second infusion of PVSRIPO 60 months after the first infusion and a third infusion of PVSRIPO 78 months after the first infusion. All patients demonstrated soap bubble degeneration on imaging, and two patients demonstrated tumor contraction. No grade 3 or higher adverse events related to PVSRIPO were observed after retreatment. Three of these patients remain alive more than 81, 80 and 52 months following the first PVSRIPO infusion and more than 9, 20 and 18 months after the second infusion, respectively. Two patients died 63 months and 20 months after the first infusion of PVSRIPO and 19.6 and 14 months after the second, respectively. The patient treated 3 times received the third infusion more than 2 months ago. Conclusions: Intratumoral reinfusion of PVSRIPO via CED is safe, and encouraging efficacy results have been observed. Clinical trial information: NCT01491893.
Phase I/II study of depatuxizumab mafodotin (ABT-414) monotherapy or combination with temozolomide in Japanese patients with/without EGFR-amplified recurrent glioblastoma.
Authors: Narita Yoshitaka , Muragaki Yoshihiro , Maruyama Takashi , Kagawa Naoki , Asai Katsunori , Kuroda Junichiro , Kurozumi Kazuhiko , Nagane Motoo , Matsuda Masahid , Ueki Keisuke , Ocampo Christopher Joseph , Matsumoto Ikiru , Odagawa Reiko , Nishimura Yasuko , Mishima Kazuhiko
Published: May 2019

2065

Background: The poor prognosis of glioblastoma (GBM; WHO grade IV) results from a high rate of disease recurrence and lack of effective treatment options. Depatuxizumab mafodotin (depatux-m, ABT-414) is comprised of an EGFR-directed antibody, depatuxizumab (depatux, ABT-806), conjugated to the microtubule toxin monomethyl auristatin F (MMAF, mafodotin). Once bounded with tumor cells, depatux-m is internalized and releases the cytotoxin, resulting in cell death. Here, we report safety, pharmacokinetic (PK) and efficacy in an ongoing phase 1/2 study of Japanese patients with/without EGFR-amplified recurrent GBM (rGBM). Methods: M13-714 (INTELLANCE-J, NCT02590263) is a non-randomized, phase 1/2 study in Japanese patients. Phase 1 assessed tolerability and PK where the dose escalation of depatux-m was from 0.5 to 1.25 mg/kg/Q2W at day 1 and 15 during 28-day cycle until progression disease (PD) or intolerable toxicity. Phase 2 assessed efficacy and safety of depatux-m in EGFR-amplified, rGBM and patients received 1.0 mg/kg of depatux-m on day 1 and 15 + 150 mg/m2 temozolomide (TMZ) on days 1-5 during each 28-day cycle until PD or intolerable toxicity. Results: As of 10 Jan 2019, 38 patients (WHO grade ≥3) were enrolled (9 in phase 1, 29 in phase 2). There was no dose limiting toxicity in phase 1. The recommended phase 2 dose was 1.25 mg/kg where the most common adverse events (AEs) were punctate keratitis in 21 patients (72%); lymphopenia in 14 patients (45%), thrombocytopenia in 13 patients (41%). Grade 3/4 AEs included thrombocytopenia and lymphopenia in 20 patients (69%). Ocular AEs were reported in 27 patients (93%) including punctate keratitis (72%). PK results (31 patients) in both phases were similar to those of non-Japanese result. Progression Free Survival (PFS) of 27 patients in phase 2 for 12 and 6 months were 8% and 27.5% respectively. The median PFS was 4 months. The overall survival (OS) for 24, 12 and 6 months were 28%, 62.5% and 93% respectively. The median OS was 15.5 months. Conclusions: Preliminary safety, PK and efficacy in Japanese patients with/without EGFR-amplified, rGBM suggests depatux-m was tolerated and showed encouraging anti-GBM effects. Clinical trial information: NCT02590263.
Results of a phase I study of bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) modified T cells for relapsed, refractory, non-Hodgkin lymphoma.
Authors: Shah Nirav Niranjan , Zhu Fenlu , Schneider Dina , Taylor Carolyn , Krueger Winfried , Worden Andrew , Longo Walter L. , Hamadani Mehdi , Fenske Timothy , Johnson Bryon , Dropulic Boro , Orentas Rimas , Hari Parameswaran
Published: May 2019

2510

Background: Anti-CD19 CAR-T cell therapy is a breakthrough treatment (tx) for patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). Despite impressive outcomes, non-response and relapse with CD19 negative disease remain challenges. Through dual B-cell antigen targeting of CD20 and CD19, with a first-in-human bispecific lentiviral CAR-T cell (LV20.19CAR), we aim to improve response rates while limiting CD19 negative relapse. Methods: Pts were treated on a Phase 1 dose escalation + expansion trial (NCT03019055) to demonstrate safety of a 41BB/CD3z LV20.19CAR T cell for adults with R/R B-cell NHL. Safety was assessed by incidence of dose limiting toxicities (DLTs) within 28 days post-infusion. Starting dose was 2.5 x 10^5 cells/kg with a target dose of 2.5 x 10^6 cells/kg. All pts received fludarabine+cyclophosphamide for lymphodepletion. Results: 11 pts have completed tx to date. 9 pts in dose escalation and 2 pts in expansion phase. Median age was 54 years (46-67) and histology included DLBCL = 5 pts, MCL = 4 pts, and CLL = 2 pts. In dose escalation, 3 pts were treated at 2.5 x 10^5 cells/kg, 3 pts at 7.5 x 10^5 cells/kg, and 3 pts at 2.5 x 10^6 cells/kg with no DLTs. As a result, 2.5 x 10^6 cells/kg was selected for expansion. In terms of safety, 6 pts developed Grade 1-2 cytokine release syndrome (CRS) and 3 pts had Grade 1-2 neurotoxicity (NTX). No patient had grade 3-4 CRS or NTX and none required ICU level care. 4 pts required 1-2 doses of tocilizumab for CRS. The day 28 overall response rate (ORR) for all pts was 82% (6/11 = complete response (CR) and 3/11 = partial response). All CR pts remain in remission, the longest > 1 year. All progressing pts underwent repeat biopsy, and all retained either CD19 or CD20 positivity. Additional pts are being enrolled in the expansion phase and updated data will be presented. Conclusions: Phase 1 results from the LV20.19 CAR T clinical trial demonstrate that infusion of 2.5 x 10^6 cells/kg is safe for further investigation with no DLTs among treated pts. Down-regulation of target antigens was not identified as a mechanism of resistance in progressing pts. With limited toxicity and encouraging ORR, dual targeted LV20.19CAR T cells merits further investigation. Clinical trial information: NCT03019055.