bluuebunny/crossref_metadata_2025_split huggingface dataset:
NCCTG N1174: Phase I/comparative randomized phase (Ph) II trial of TRC105 plus bevacizumab versus bevacizumab in recurrent glioblastoma (GBM) (Alliance).
Authors: Galanis Evanthia , Anderson S. Keith , Butowski Nicholas A. , Hormigo Adilia , Schiff David , Tran David Dinh , Omuro Antonio Marcilio Padula , Jaeckle Kurt A. , Kumar Shaji , Kaufmann Timothy J. , Buckner Jan C. , Twohy Erin , Giannini Caterina , Wen Patrick Y. 
Published: September 2018

2023 Background: TRC105 is a humanized antibody targeting CD105 (endoglin), a member of the TGFβ receptor superfamily. CD105 is expressed in glioma stem cells and circulating endothelial cells (CECs) in GBM patients (pts), increasing following VEGF inhibition. N1174 was conducted in recurrent bevacizumab (bev) naïve GBM pts to investigate the hypothesis that CD105 blockade+bev can delay development of bev resistance. Methods: After a ph I cohort (15 pts) established the ph II dose of TRC105 as 10 mg/kg IV over 4 hours every 7 days in combination with standard dose bev, the ph II trial used 1:1 randomization with 90% power and 0.10 type I error to detect a 3 month (mo) difference in progression-free survival (PFS) between the two arms. CECs including CD105 positive subsets were measured by flow cytometry at baseline and multiple time points. Results: Based on 101 evaluable ph II pts, there was no significant difference in PFS between TRC105+bev and bev only (2.9 vs 3.2 mo, respectively; HR=1.14, 95% CI 0.73-1.77, p=0.57), or overall survival (10.0 vs 7.4 mo; HR 1.02 95% CI 0.63-1.65, p=0.93). Response rate (complete or partial) was 12.2% (6/49) for TRC105+bev and 11.6% (5/43) for bev only. Overall incidence of grade (gr) 3+ toxicity was higher for TRC105+bev (67.3% vs 32.7%, p<0.001) mainly due to 14 pts with gr 3 anemia in the TRC105+bev arm vs 0 in the bev only pts. Gr 3+ non-heme toxicities were higher in pts receiving TRC105+bev vs bev only (50% vs 30.6%, p=0.07), mainly due to headache (6 vs 1 pts) and hyperglycemia (3 vs 0 pts). CECs remained stable in combination treated pts, suggesting a possible impact of the anti-CD105 blockade, but increased at progression in the bev only arm. There was no association between PFS and initial changes in CEC values, independent of treatment received. Conclusions: TRC105 plus bev did not prolong median PFS vs single agent bev in recurrent GBM pts, although it was associated with a non-significant prolongation of OS. These data and associated correlative analysis of CECs from study pts point against endoglin being a clinically significant factor for the development of bev resistance. Support: U10CA180821, U10CA180882. Clinical trial information: NCT01648348.
SHADOW study: Comparison of conventional clinical follow-up with clinician led video follow-up in newly diagnosed patients with intermediate and high grade glioma receiving adjuvant temozolomide therapy.
Authors: Patil Vijay Maruti , Pande Nikhil , Chandrasekharan Arun , Tonse Raees , MV Chandrakanth , Krishnatry Rahul , Ghanekar Shamika , Bano Nazia , Sastri Jayant , Gupta Tejpal , Jalali Rakesh 
Published: September 2018

2024 Background: In patients with gliomas, nurse led telephonic follow-up was associated with high satisfaction rates and was a valid alternative approach to conventional hospital based follow-up. However, other alternative forms of follow-up have not been studied in patients on active treatment. Methods: SHADOW was a prospective, randomized trial (CTRI/2017/01/007626). Adult intermediate to high grade glioma patients on adjuvant temozolomide with facilities for live video call were invited. After their consent, patients underwent a video follow-up (VF) 4 days prior to clinical follow-up (CF). The decisions taken during the VF and CF were noted in 5 domains, relating to temozolomide decisions (primary endpoint), concurrent medications, need for imaging, molecular testing and rehabilitation. Clinicians performing VF or CF were randomly assigned and were blinded for the other arm decisions. Patients satisfaction and costs incurred in each type of follow-up was documented. The planned sample size was 65, assuming an alpha of 0.05, a kappa coefficient of 0.9 with a one sided CI for lower limit of 0.6 and assuming a 20% lost to follow up rate. Agreement analysis was performed for calculation of Cohen's kappa coefficient. Results: 112 patients were screened and 65 were accrued. All patients underwent both VF and CCF. The concurrence in decision of administering temozolomide between VF and CCF was 100% (Cohen kappa = 1.0, 95%CI 1.0-1.0, p < 0.00). In concurrent medication domain (k = 0.66,95% CI 0.04 -1, p < 0.00), imaging domain (k = 1.0, 95%CI 1.0-1.0, p < 0.00), rehabilitation domain (k = 1.0, 95%CI 1.0-1.0, p < 0.00) and molecular testing domain (k = 0.65, 95% CI 0.20-1, p < 0.00), the agreement was substantial. The satisfaction rate was 100% post video follow up and was 98.5 % post clinical follow up. The median cost incurred in VF was 58.15 USD (IQR 43.38-91.69) while that incurred in CCF was 131.23 USD (IQR 68.8-256 (p < 0.00)). Conclusions: The decisions taken regarding administration of adjuvant TMZ were similar between VF and CCF. Hence, it's practical and economical to substitute CCF with VF during adjuvant TMZ administration. Clinical trial information: CTRI/2017/01/007626.
Is less more? Comparing chemotherapy alone to chemotherapy and radiation for high risk, grade II glioma—An analysis of the National Cancer Data Base.
Authors: Jhaveri Jaymin , Liu Yuan , Gillespie Theresa Wicklin , Chowdhary Mudit , Buchwald Zachary , Olson Jeffrey J. , Voloschin Alfredo Daniel , Shu Hui-Kuo George , Crocker Ian R. , Curran Walter John , Patel Kirtesh R. 
Published: September 2018

2031 Background: Grade II glioma patients with subtotal resection (STR) or age ≥ 40 are considered high risk. RTOG 9802 demonstrated that for these high-risk patients, chemotherapy and radiation therapy improved overall survival (OS) compared to radiation alone. The purpose of this study is to compare the OS of high risk, grade II glioma patients treated with adjuvant chemotherapy alone (CA) to chemotherapy and radiation therapy (CRT). Methods: Using the National Cancer Data Base (NCDB), high risk (age ≥ 40 or STR) grade II glioma patients with oligodendroglioma, astrocytoma, or mixed tumors were identified. Patients receiving CA were compared to patients receiving CRT. Univariate and multivariable analyses (MVA) were performed. Propensity score (PS) matching was utilized to account for difference in patient characteristics. Kaplan Meier statistics were utilized to compare OS. Results: 1054 high risk, grade II glioma patients were identified, 47.1% receiving CA and 52.9% receiving CRT. Median follow up time was 55.1 months. Patients treated with CA were statistically more likely (all p < 0.05) to be oligodendroglioma histology (65.5% vs. 34.2%), 1p/19 co-deleted (22.8% vs. 7.5%), younger median age (47 vs. 48 years) and treated at an academic program (65.2% vs. 50.3%). MVA demonstrated treatment type was not a significant predictor for OS (p = 0.125), while tumor size > 6cm, astrocytoma histology, and older age were predictors for worse survival (all p < 0.05). Utilizing 1:1 PS matching, with 662 total patients, OS was statistically similar (p = 0.919) for CA and CRT at 5 years (69.1% vs. 68.5%, respectively) and 7 years (55.5% vs. 60.0%, respectively). Conclusions: In this retrospective analysis of the NCDB, long term OS for high-risk, grade II glioma patients treated with CA appears similar to CRT. These findings are hypothesis generating, with the standard of care still remaining CRT as established by RTOG 9802. Prospective clinical trials comparing CA and CRT are warranted.
TERT promoter mutations in progressive treatment-resistant meningiomas.
Authors: Juratli Tareq A. , Thiede Christian , Krex Dietmar , Brastianos Priscilla Kaliopi , Wakimoto Hiroaki , Schackert Gabriele , Kirsch Matthias , Cahill Daniel P. 
Published: September 2018

2047 Background: Recurrent meningiomas often undergo a grade-progression to become atypical or malignant upon recurrence. Detailed study of progressive meningioma has been hampered by the lack of available paired specimens. Here, we sequenced the TERT promoter ( TERTp) in a large series of patients with treatment-resistant meningiomas at initial diagnosis as well as their sequential recurrences. Methods: We scored 77 meningiomas from 36 patients for TERTp mutations. All patients in this study developed recurrences during the median follow-up of 13.3 years (range 6.4 - 25.5 years) and underwent three surgeries on average (range 2-8). Additionally, we screened geographically distinct sites of all TERTp-mutant meningiomas to interrogate intratumoral heterogeneity. Results: TERTp mutations were detected in 18 tumor samples (18/77 = 23.3%) from 12 patients, but not in any of the matched blood sample DNAs, excluding germline mutations. Notably, the TERTp mutations were absent in the initial lower-grade tumor and were present in the subsequent recurrent tumors. Moreover, we observe emergent spatial heterogeneity in the form of mixed populations of recurrent tumor cells containing different mutation status of the TERT promoter gene in three cases. Patients with emergence of TERTp -mutant meningiomas had a significantly shorter overall survival than their TERTp wild-type counterparts, when measured from the time of initial diagnosis (2.4 vs 11.1 years, 95% CI 0.25-4.54 vs 9.3- 16.8 years p = 0.007). Conclusions: Our data confirm the high frequency of TERTp mutations and the emergence of TERT promoter mutation in recurrent progressive meningiomas, strongly indicating the presence of ongoing evolution impacting the natural history of these tumors. TERTp mutations are mostly associated with poor outcome. Finally, our study provides important insight into the complexity of tumor heterogeneity and has important implications for targeted therapy in treatment-resistant meningiomas.
Whole exome sequencing and copy-number variation analysis of 20 NF2-associated spinal and cranial meningiomas.
Authors: Dewan Ramita , Pemov Alexander , Hansen Nancy F , Chandrasekharappa Settara C , Mullikin Jim , Boland Joseph F , Asthagiri Ashok R , Stewart Douglas ,   NISC
Published: September 2018

2051 Background: Neurofibromatosis type 2 is a heritable tumor predisposition syndrome characterized by the growth of multiple tumor types in the nervous system, including bilateral vestibular schwannomas, meningiomas and ependymomas. Recent genomic sequencing studies have revealed that NF2 inactivation is the most frequent genetic event in sporadic meningiomas. In line with Knudson’s hypothesis, it is accepted that somatic inactivation of the wildtype NF2 allele initiates tumor growth in NF2 patients, but little is known of what other genes or pathways influence meningioma tumorigenesis. Methods: To investigate this question, we performed whole exome sequencing (WES) (Illumina Hi-Seq 2500 platform, 96 Mb SeqCap EZ Exome + UTR Library, NimbleGen) and SNP-array analysis (HumanOmniExpressExome-8, v1.2 arrays, Illumina) of twenty spinal and cranial meningioma samples from seven NF2 patients. Mutation validation was completed via orthogonal sequencing (IonTorrent, ThermoFisher). Results: We identified NF2 germline mutations in all patients, including five nonsense, one splice site and one likely pathogenic intronic mutation. We found that the predominant mechanism of somatic NF2 inactivation in the tumors was loss of heterozygosity (LOH): we identified large chromosome 22 deletions containing NF2 in nineteen out of twenty meningiomas. The second most frequent chromosomal aberration was a deletion within chromosome 1p, followed by entire chromosome X deletion and rearrangements in chromosome 17q. The remaining samples exhibited normal diploid genomic architecture. Somatic mutations included about twenty point substitutions and small indels. Conclusions: Our study revealed that somatic inactivation of NF2 is the most frequent and only recurrent genetic event in NF2-associated meningiomas. Large LOH events are the most prevalent second hit mechanism and may also represent a common path of meningioma progression. Somatic single nucleotide substitutions and small indels are rare in these tumors. Interestingly, we did not identify mutations in TRAF7, KLF4, AKT1, or SMO, which have been found to be critical for non-NF2 meningioma growth.
Treatment through progression with ofranogene obadenovec (VB-111), an anti-cancer viral therapy, significantly attenuates tumor growth in recurrent GBM: Individual phase 2 patient data.
Authors: Brenner Andrew Jacob , Wen Patrick Y. , Vredenburgh James J. , Peters Katherine B. , Blumenthal Deborah T. , Freedman Laurence S , Oberman Bernice , Lowenton-Spier Noa , Lavi Michal , Harats Dror , Cohen Yael Chava 
Published: September 2018

2055 Background: Ofranergene obadenovec (VB-111) is a viral cancer-therapy with a dual mechanism: vascular disruption and induction of a tumor directed immune response. Prolongation of overall survival (OS) has been shown in recurrent glioblastoma (rGBM) patients treated through progression with VB-111 in combination with bevacizumab (BEV) compared to historical controls and to patients with limited exposure (LE) to VB-111. Here we present individual patient tumor growth data. Methods: VB-111 was administered at 1x1013viral particles bimonthly until progression, followed by BEV standard of care (LE cohort). The protocol was amended to allow treatment through progression (TThP) with VB-111 bimonthly, with the addition of BEV 10mg/Kg biweekly, until further progression (TThP cohort). Tumor dimensions were assessed q2 months by MRI locally and by an independent central lab. The slope of the log tumor measurement over time was calculated for each patient, average slopes were compared across therapy groups using the Wilcoxon Rank Sum test. Results: 46 patients received up to 13 doses of VB-111. All started with VB-111 monotherapy. 22 were included in the LE cohort; 24 in the TThP cohort. Cohorts were comparable by measures of age, performance status, prior lines of therapy, baseline tumor dimensions and progression-free-survival. Spider diagrams demonstrate similar rapid tumor growth in both LE and TThP cohorts during the VB-111 monotherapy period (local site data; median % increase (MPI) per 30d: 14.8 vs 14.1, p = 0.98). In the TThP cohort, growth was attenuated after the 1stprogression, compared to the preceding VB-111 monotherapy period (MPI: 0.6 vs 14.1, p = 0.0032); responses were seen, including 2 complete responses (CR), one patient remaining in CR over 3 years. A similar attenuation was seen in central lab tumor measurements. Conclusions: Treatment through progression with VB-111 in combination with BEV induced durable tumor growth attenuation, which was associated with prolonged OS of 15 months in patients with rGBM. The GLOBE phase 3 randomized controlled trial of VB-111 in rGBM is currently underway. Clinical trial information: NCT01260506.
Heterogeneous spectrum of childhood and adult SHH medulloblastoma: Clinical, radiogenomic features, patterns of failure and survival.
Authors: Jalali Rakesh , Dasgupta Archya , Shirsat Neelam , Sridhar Epari , Pungavkar Sona , Chinnaswamy Girish , Sastri Jayant , Krishnatry Rahul , Gupta Tejpal 
Published: September 2018

2063 Background: To present SHH pathway driven medulloblastoma (MB) diversities in pediatric and adult patient populations. Methods: 60 patients with SHH-MB seen at our institute during 2009-2015. We assigned 22 predefined radiological features for all MB subgroups including SHH. Outcome data was retrieved from a prospectively maintained database. Results: Median age of entire cohort was 14 years (1-48 years). 29 were adults (a-SHH) and 31 were pediatric SHH (p-SHH). Radiological data available for 39 patients showed a-SHH having lateralised location in 72% cases. Distinct MRI features to predict SHH include mild/moderate contrast enhancement (90%), cystic changes (82%), edema (92%); identical in two age groups. We could predict SHH accurately 95% times. p-SHH were seen to have higher frequency of p53 mutations (70% vs 45%). At median follow-up of 37 months, 25 patients failed [isolated tumor bed (TB) in 10, TB and supratentorially in 2, cranium outside TB in 1, craniospinal in 5 (along with TB), extraneuraxial (ENM) in 5, second primary in 2 (lymphomas)]. 1 and 3 year DFS was 74% (p-SHH) vs 96% (a-SHH) and 58% vs 73% respectively (p-0.19). The failures seen in a-SHH were typically late (10/11 failed > 22 months) as compared to p-SHH (12/14 failing < 24 months). Also location of recurrences was different, with 7 of a-SHH failing at TB and rest 3 developed ENM. Ten of 13 in p-SHH failed beyond TB. Post- recurrence salvage was better in a-SHH compared to p-SHH, 1-year survival of 50% vs 19% (p-0.08). Overall survival at 1 and 3 year 84% and 55% for p-SHH and 100% and 88% for a-SHH respectively (p = 0.04). Histology and tumor location significantly correlated with OS. No significant correlation was seen with CSI dose or chemotherapy. Conclusions: SHH medulloblastoma have unique MRI features and can be predicted up to 95% times pre-operatively. Adult and pediatric SHH MB form extreme diverse groups with different patterns of failure reflecting different tumor kinetics. Adults fail primarily over TB after initial 2 years. Paediatric SHH follow aggressive course with early disseminated recurrences in 1st year. Different treatment modalities may be needed for pediatric and adult SHH MB.
Ceritinib plus nivolumab (NIVO) in patients (pts) with anaplastic lymphoma kinase positive (ALK+) advanced non-small cell lung cancer (NSCLC).
Authors: Felip Enriqueta , De Braud Filippo G. , Maur Michela , Loong Herbert H. F. , Shaw Alice Tsang , Vansteenkiste Johan F. , John Tom , Liu Geoffrey , Lolkema Martijn P. , Scott Jeffrey W. , Yu Richard , Selvaggi Giovanni , Mishra Kaushal , Lau Yi-Yang Yvonne , Tan Daniel Shao-Weng 
Published: September 2018

2502 Background: Induction of PD-L1 expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring EML4–ALK rearrangements. Here we explore whether the combination of ALKi (ceritinib) and PD1-inhibitor (NIVO) will provide sustained clinical benefit to pts with ALK+ NSCLC. Methods: This phase 1 dose escalation study enrolled previously treated (ALK inhibitor [ALKi] or chemotherapy) or tx-naive pts with stage IIIB/IV ALK+ NSCLC; who received NIVO 3 mg/kg IV Q2W + ceritinib with low-fat meal, at 450 mg/day (group 1) or 300 mg/day (group 2) until progression/unacceptable toxicity. Primary objective: MTD/recommended dose for expansion. Dose escalation was guided by Bayesian logistic regression model with overdose control. Results: Median follow-up: group 1 (n = 14) 13 mos (10-15); group 2 (n = 22) 6 mos (2-10). As of 9 Sep 2016, 16/36 (44%) pts discontinued tx: disease progression (11 [31%] pts), AE’s (3 [8%] pts), and death (2 [6%] pts). In group 1, 4 pts experienced DLT: pancreatitis (n = 2), lipase and transaminase increase (n = 1), and autoimmune hepatitis (n = 1). In group 2, 2 pts experienced DLT: G3 ALT increase. Both dose levels met Bayesian criteria for dose expansion. Overall most frequent (≥40%) AEs (n = 36), were diarrhea (64%), ALT increase (56%), AST increase (44%) and vomiting (42%). Most frequent ( > 10%) grade ≥3 AEs were increases in ALT (22%), GGT (17%), amylase (11%), and lipase (11%), and maculopapular rash (11%). Incidence of rash (grouped term) was 61%; similar in both groups. Grade 3 rash was reported in 29% pts in group 1 and 14% pts in group 2. Preliminary ceritinib steady state PK (AUC0-24 and Cmax) suggested that 300 mg/day exposure was ~ 70-75% of 450 mg/day. Confirmed (c)/unconfirmed (u) ORR: ALKi-pretreated pts (group 1 [n = 8], group 2 [n = 12]) was 63% (4 cPR,1 uPR; 95% CI: 25%, 92%), and 33% (4 uPR) 95% CI: 10%, 65%) respectively; ALKi-naïve pts, (group 1 [n = 6], group 2 [n = 10]) was 83% (5 cPR; 95% CI: 36%, 100%), and 70% (1 cCR, 3 cPR 3uPR; 95% CI: 35%, 93%) respectively. Conclusions: Ceritinib + NIVO is an active combination in ALK+ NSCLC. However, the protocol will be amended to address observed toxicities. Data will be updated for presentation. Clinical trial information: NCT02393625.
Development of a population pharmacokinetic (PPK) model of intravenous (IV) trastuzumab in patients with a variety of solid tumors to support dosing and treatment recommendations.
Authors: Kirschbrown Whitney Paige , Quartino Angelica Linnea , Li Hanbin , Mangat Ranvir , Wada D Russell , Garg Amit , Jin Jin Y , Lum Bert L. 
Published: September 2018

2525 Background: The aim of this analysis was to develop a PPK model for IV trastuzumab (Herceptin), to assess the impact of patient covariates on PK, and perform simulations to support dosing recommendations. Methods: Serum trastuzumab concentration data (26,040 samples) from 1582 patients with metastatic breast cancer (MBC), early breast cancer (EBC), advanced gastric cancer (AGC) or other tumor types, and 6 healthy volunteers in 18 Phase I, II, and III trials were analyzed using nonlinear mixed-effects modeling (NONMEM). Monte Carlo simulations were performed using the NONMEM PK parameter estimates (with variability) to inform dosing recommendations. Results: A two-compartment model with parallel linear and nonlinear elimination best described the data. Significant covariates (P < 0.001) influencing linear CL were baseline weight, SGOT, albumin, primary tumor type, and presence of liver metastases. MBC had similar PK parameters as EBC, with lower distributions of Cmin,ss in MBC explained by covariates. The higher linear CL in AGC patients resulted in a 30.5% lower Cmin,ss. Simulations for drug washout indicated that 95% of patients with breast cancer (BC) reach trastuzumab concentrations < 1 µg/mL (~97% washout) at ≤7 months. Simulations also indicated that a missed dose of trastuzumab in BC or AGC patients of ≤1 week did not result in a long PK under-exposure (i.e. the trastuzumab concentration is within 15% of Cmin,ss by 3 weeks) but a missed dose of > 1 week took approximately 6 weeks to get back within the steady-state exposure range. Conclusions: Trastuzumab PK was well described by a two-compartment model with parallel linear and nonlinear eliminationacross cancer types, disease status, and regimens. No dose adjustment is required based on any of the identified patient covariates (e.g. weight, tumor type). Simulations using the PPK model informed the prescribing information for Herceptin; trastuzumab has a 7-month serum washout period during which patients should avoid an anthracycline-based therapy, pregnancy, or breastfeeding. A re-loading dose is required if a maintenance dose is missed by > 1 week to maintain serum concentrations.