bluuebunny/crossref_metadata_2025_split huggingface dataset:
RADT-20. SINGLE INSTITUTION REVIEW OF LARGE VOLUME HIGH GRADE GLIOMA PATIENTS TREATED WITH RADIOTHERAPY
Authors: Manik Vishal , Swampillai Angela , Al-Salihi Omar , Chia Kazumi , Brazil Lucy 
Published: November 2021

Abstract

AIM
Not uncommonly, we come across significantly large high grade glioma cases (HGGs). With standard delineation protocols, we end up irradiating a large volume of normal brain. Emami & QUANTEC data define normal brain tolerance doses, however they are often of limited use in clinic practice. Thus, we reviewed our patients with significant tumor volumes to derive a safe dose/ volume level for brain.

METHODOLOGY
Patients with HGGs over the last 3 years were extracted from Mosaiq™ information system. The output was sorted with respect to clinical target volumes from lowest to highest. The top 25 percentile i.e. patients with a CTV of &gt; 412cc (n=53) were identified for this study. Data was collected with respect to clinical, tumor characteristics and radiotherapy parameters.

RESULTS
Median age of population was 53 and majority (n=38) were males. Nine patients had multi-focal tumors while six had bilateral extension. Majority of the study group had Glioblastoma Multiforme (n=44), whereas 6 had Grade 3 tumors. Most of the patients could only have a biopsy (n=27). Molecular profile showed 42 were Isocitrate-Dehydrogenase negative and 26 were unmethylated tumors. Stupp’s & Perry’s regimen were the commonly used protocols, however patients (n=7) with significant volumes near critical structures were treated with doses in the range of 50.4 – 55Gy in 30 fractions. The CTV volumes in the population ranged from 412 – 1223 cc while total brain volume range was 1112 – 1667 cc. Median of 43.5% of brain volume was covered in the PTV, while median of 5% of brain volume outside the PTV was treated to BED2 of 100Gy. Median survival was 12.4 months.

CONCLUSION
Our study shows reasonable tolerance of radiotherapy doses of &gt; 50 Gy to larger volumes of brain. We propose a multi-center collaborative study to derive a new standardized dose volume tolerance.
RADT-21. DUAL FET PET-GUIDED SIB IN RADIOTHERAPY OF NEWLY DIAGNOSED GLIOBLASTOMA - A PILOT STUDY
Authors: Harat Maciej , Blok Maciej , Wiatrowska Izabela , Furtak Jacek , Małkowski Bogdan 
Published: November 2021

Abstract

BACKGROUND
PET using FET is a valuable tool to determine the actual glioblastoma infiltration.The FET-PET examination can be performed using the dual-time point acquisition of FET . Infiltration defined in dual FET PET corresponds to the location and shape of the recurrence. The aim of this study was to evaluate safety and efficacy of simultaneous integrated boost based on dual FET PET combined with temozolomide TMZ for the postoperative treatment of GBM.

METHODS AND MATERIALS
In a prospective pilot study, 17 patients were enrolled. All patient presented an active tumor in postoperative PET imaging. The radiotherapy was performed as an FET-PET-based integrated-boost IMRT. The prescribed dose was 78 and 60 Gy (single dose 2.6 and 2.0 Gy, respectively). The progression-free survival (PFS) and overall survival (OS), toxicities and radiation necrosis rate were evaluated.

RESULTS
The median follow up was 37 months.Two patients were found to have uncontrolled seizures during radiation treatment and were not able to received treatment per protocol. Patients treated per protocol presented new or increased neurological deficits in 7/15 cases in a month after irradiation. In 4 patients radiation necrosis was confirmed in pathological report after re-surgery. Three patients were still alive after 26,28 and 38 months of follow up without progression and any signs of treatment related late toxicity. The 2-year survival rate was 43% in all patients treated per protocol. Median overall survival (OS) and disease-free survival (DFS) were 20 and 12 months, respectively. In a subgroup of MGMT methylated and unmethylated the median survival was 25 and 12 months.

CONCLUSIONS
Our dose escalation concept with a total dose of 78 Gy, based on FET-PET, have lead to promising survival results even within MGMT unmethylated subgroup. However rate of early toxicity and radiation necrosis is high.
RADT-31. TREATMENT TRENDS AND SURVIVAL OUTCOMES IN ATYPICAL MENINGIOMA
Authors: Syed Yusef , Rupji Manali , Switchenko Jeffrey , Eaton Bree , Olson Jeffrey , Kimberly Hoang , Bray David , Shu Hiu-Kuo , Zhong Jim 
Published: November 2021

Abstract

BACKGROUND
WHO grade II (atypical) meningiomas are treated with surgical resection, often followed by adjuvant fractionated radiation therapy (FRT). The increased availability of frameless stereotactic radiosurgery (SRS) presents an opportunity to offer patients a high biological effective dose over fewer fractions. Here we study the patterns of care and outcomes of these two forms of adjuvant RT.

METHODS
Patients with atypical meningioma were abstracted from the National Cancer Database (NCDB). Descriptive statistics were reported, and differences between treatment groups were assessed using either a chi-square test or ANOVA. Patients were grouped by treatment type and Kaplan Meier (KM) analysis was performed to compare overall survival (OS) using a log rank test. Univariable (UVA) and multivariable (MVA) cox regression analyses were completed.

RESULTS
Of 10,015 cases diagnosed from 2004-2016, 7,153 received surgery alone, 2,059 received surgery and adjuvant FRT (S+RT), and 362 received adjuvant SRS (S+SRS). The use of adjuvant RT increased by 71.8% for S+RT and 97.8% for S+SRS. In 2004, 15.1% of 443 registered patients received S+RT and 2.26% received S+SRS, while in 2016 these figures were 26.0% and 4.47%, respectively, for the 1051 registered patients (p&lt; 0.001 and 0.022, respectively). For the 8,636 patients with survival data there was no significant difference in median OS between S+RT and S+SRS (130 months vs. 125 months, log rank p=0.935). On UVA, S+RT conferred better survival compared to surgery alone (HR 0.81 [0.72-0.91], p&lt; 0.001) while S+SRS trended towards better survival (HR 0.82 [0.64-1.06], p=0.124). On MVA, no significant OS benefit was seen with S+RT (HR 0.96 [0.85-1.08], p=0.491) or S+SRS (HR 0.90 [0.69-1.16], p=0.413) versus surgery alone.

CONCLUSIONS
While the use of adjuvant RT for atypical meningioma has increased substantially since 2004, OS is comparable between FRT and SRS. The data presented here support further prospective investigation of adjuvant SRS.
CTIM-02. PHASE II STUDY OF IPILIMUMAB AND NIVOLUMAB IN LEPTOMENINGEAL CARCINOMATOSIS
Authors: Strickland Matthew , Lee Eudocia Quant , Wang Nancy , Cohen Justine , Chukwueke Ugonma , Forst Deborah , Eichler April , Overmoyer Beth , Lin Nancy , Chen Wendy , Bardia Aditya , Juric Dejan , Dagogo-Jack Ibiayi , White Michael , Dietrich Jorg , Nayyar Naema , Kim Albert , Alvarez-Breckenridge Christopher , Mahar Maura , Mora Joana , Nahed Brian , Jones Pamela , Shih Helen , Gerstner Elizabeth , Giobbie-Hurder Anita , Carter Scott , Oh Kevin , Cahill Daniel , Sullivan Ryan , Brastianos Priscilla 
Published: November 2021

Abstract
Leptomeningeal disease (LMD) is an increasingly common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We conducted a single arm Phase II study of combined ipilimumab and nivolumab in patients with LMD from solid tumor malignancies (NCT02939300). Patients received manufacturer-specific dosing regimens of combined ipilimumab and nivolumab based on primary-tumor histology until definitive progression or unacceptable toxicity. The primary end point was rate of overall survival at 3 months (OS3). A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Eighteen patients with diverse primary tumor histologies were enrolled and all received at least one dose of combined ipilimumab and nivolumab. Median follow up based on patients still alive was 8.0 months (range: 0.5 to 15.9 months). The study met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients were alive at three months after enrollment. One third of patients experienced one (or more) grade-3 or higher adverse events possibly related to treatment. Two patients discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events overall included fatigue (N=7), nausea (N=6), fever (N=6), anorexia (N=6) and rash (N=6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients; this therapeutic approach should be studied in larger, multicenter clinical trials to validate these results as well as better identify patients who will benefit.
CTIM-05. A PHASE 1/2 STUDY OF THE COMBINATION OF INDOXIMOD AND TEMOZOLOMIDE FOR ADULT PATIENTS WITH TEMOZOLOMIDE-REFRACTORY PRIMARY HIGH-GRADE GLIOMAS
Authors: Lukas Rimas , Phuphanich Surasak , Rudnick Jeremy , Colman Howard , Cohen Adam , Monga Varun , Milham Mohammed , Sahebajam Solmaz , Kennedy Eugene , Smith Christopher , Rixe Olivier 
Published: November 2021

Abstract

BACKGROUND
Optimal management of progressive high-grade gliomas (HGG) is not fully defined and outcomes are poor. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme which converts tryptophan to kynurenines, which contribute to the immunosuppresive tumor microenvironment (TME). Targeting the TME by inhibiting IDO1 is a strategy for potential improvement in survival in HGG.

METHODS
A phase 1/2 trial using the IDO1 inhibitor indoximod was conducted in progressive grade 3 and 4 gliomas. The phase 1 cmponent used a 3 + 3 design escalating indoximod from 600mg po BID to 1200mg po BID in conjunction with temozolomide (150 mg/m2, 5/28 days). The phase 2 component consisted of 3 cohorts: A) indoximod+temozolomide B) indoximod+temozolomide+bevacizumab (patients already on bevacizumab) C) indoximod+temozolomide+stereotactic radiosurgery (SRS). Patients were treated until progression or toxicity.

RESULTS
33.3% of patients developed indoximod TEAEs. There were no dose limiting toxicities in the phase 1 component (n=12). 1200 mg BID was established as the phase 2 dose of indoximod. In the phase 2 component (n=148) PFS6 was 74% (A), 93% (B), 70% (C). Median OS was 289 days [10.3 months](A), 159 days [5.7 months](B), 285 days [10.2 months](C). Correlative study results will be available for meeting presentation.

CONCLUSIONS
The IDO1 inhibitor indoximod proved safe and tolerable in conjunction with temozolomide, bevacizumab, and SRS in patients with progressive HGG. There was a trend toward better survival outcomes when indoximod was combined with temozolomide alone or temozolomide+SRS.
CTIM-07. A PHASE I/II STUDY EVALUATING THE SAFETY AND EFFICACY OF A NOVEL LONG-ACTING INTERLEUKIN-7, NT-I7, FOR PATIENTS WITH NEWLY DIAGNOSED HIGH-GRADE GLIOMAS AFTER CHEMORADIOTHERAPY
Authors: Campian Jian , Butt Omar , Luo Jingqin , Avvaru Chandini , Katumba Ruth , Zhou Alice , Kim Albert , Dunn Gavin , Abraham Christopher , Yang Se Hwan , Fan Jean , Lee Byung Ha , Ranjitkar Sunita , Le NgocDiep , Ansstas George , Johanns Tanner , Rettig Michael , Chheda Milan , Huang Jiayi 
Published: November 2021

Abstract

BACKGROUND
Lymphopenia is common after standard radiation therapy (RT) and temozolomide (TMZ) in high-grade gliomas (HGG) and correlates with shorter survival. Interleukin-7 (IL-7), a T-cell proliferation cytokine, is inappropriately low in HGG patients. Our previous preclinical studies demonstrated that NT-I7 (efineptakin alfa), a recombinant human IL-7, corrects lymphopenia and improves survival in murine glioma models. This study examines the safety and absolute lymphocyte counts (ALCs) following administration of NT-I7 patients with newly diagnosed HGG.

METHODS
Patients with HGG receiving RT/TMZ with ALC ≥600 were eligible. NT-I7 was administered intramuscularly within 1 week after completion of concurrent RT/TMZ and then every 12 weeks, for up to 4 total doses. Phase I examined 6 dose levels (60, 120, 240, 540, 720, and 960 mcg/kg) using the accelerated-titration design for the first 2 doses and 3 + 3 design thereafter to identify the maximum tolerated dose (MTD). Phase II is a double-blinded, placebo-controlled study with 10 HGG patients per arm comparing changes in ALC. Immune profiling will be performed with CyTOF and cytokine analysis.

RESULTS
Phase I is complete, with 19 patients (89% GBM, median age: 58 (range: 25-78), median baseline ALC: 1000 cells/mm3, median dexamethasone: 0 mg/day (range: 0-12)). The median number of NT-I7 doses administered was 2 (range: 2-4). The most common treatment-related adverse event was grade 1 or 2 injection site reactions (42%). Two patients had dose-limiting toxicities at 960 mcg/kg (grade 3 elevated alanine aminotransferase and grade 3 back pain), prompting selection of 720 mcg/kg for phase II. Dose-dependent increases in ALC were observed at 4 weeks ranging from 1.3x to 4.1x. Phase II enrollment is ongoing.

CONCLUSIONS
NT-I7 is well tolerated when administered after chemoradiotherapy for HGG patients with MTD of 720 mcg/kg and demonstrates dose-dependent increase of ALC. Phase II and immune profiling are ongoing. Clinical Trial ID: NCT03687957.
CTIM-19. TEM-GBM: A PHASE I-IIA DOSE-ESCALATION STUDY DELIVERING IFN-Α WITHIN GLIOBLASTOMA MULTIFORME TUMOR MICROENVIRONMENT BY GENETICALLY MODIFIED TIE-2 EXPRESSING MONOCYTES
Authors: Finocchiaro Gaetano , Gentner Bernhard , Marica Eoli , Francesca Farina , Capotondo Alessia , Ferla Valeria , Carrabba Matteo , Cuccarini Valeria , Meco Francesco Di , Legnani Federico , Pollo Bianca , Saini Marco , Ferroli Paolo , Pallini Roberto , D'Alessandris Giorgio , Patanè Monica , Paterra Rosina , Garramone Mariagrazia , Antonarelli Gabriele , Naldini Matteo , Barcella Matteo , Brambilla Valentina , Magnani Tiziana , Mazzoleni Stefania , Bashir Zahid , Olivi Alessandro , Bruzzone Mariagrazia , Russo Carlo , Naldini Luigi , Ciceri Fabio 
Published: November 2021

Abstract
Temferon is an ex vivo gene therapy consisting of autologous HSPCs genetically modified to deliver IFN-α2 within the tumor microenvironment (TME) by Tie-2 expressing macrophages. TEM-GBM is an open-label, Phase I/IIa dose-escalation study evaluating safety and efficacy of Temferon in up to 21 newly diagnosed GBM patients with unmethylated MGMT. Autologous HSPCs are transduced with a LVV encoding for IFN-a2 gene. As of 30th April 2021, 18 patients have been enrolled; 13 received Temferon (D+0) with follow-up of 8 – 662 days. After conditioning and Temferon infusion, a rapid engraftment and hematological recovery occurred, with median neutrophil and platelet engraftment at D+13 and D+12, respectively. No dose limiting toxicities were reported. Temferon-derived cells were found within 14 days post treatment and persisted albeit at lower levels in the long-term. Five deaths occurred: one at +478, three at +322, +340 and +402 days due to PD, and the fourth at +60 due to complications following the conditioning regimen. Eight patients had PD (-12 to +239). SAEs include respiratory tract infections, pulmonary embolism, CMV and C.Diff infections, febrile neutropenia, hemiparesis, seizure, brain abscess, worsening of performance status and respiratory failure compatible with ASCT, concomitant medications and PD. Four patients underwent second surgery. Recurrent tumors had gene-marked cells present and increased expression of ISGs compared to diagnosis, indicative of local IFNa release by TEMs. In one patient, a stable lesion had a higher proportion of T cells and TEMs within the myeloid infiltrate and an increased IFN-response signature than in a progressing lesion. Characterization of T-cell immune repertoire suggests the expansion of tumor-associated clones. TME characterization by scRNA and TCR sequencing is ongoing. Interim results show that Temferon is well tolerated, with no dose limiting toxicities identified to date and provide initial evidence of potential immune system activation within the TME.
CTNI-07. ABTC-1701: PILOT SURGICAL PK STUDY OF BGB324 (BEMCENTINIB) IN RECURRENT GLIOBLASTOMA PATIENTS – RESULTS FROM INTERIM FUTILITY ANALYSIS
Authors: Burt Nabors L , Nakano Ichiro , Supko Jeff , Lobbous Mina , Grossman Stuart , Ye Xiaobu , Desideri Serena , Danda Neeraja , Fisher Joy , Strowd Roy , Walbert Tobias 
Published: November 2021

Abstract

BACKGROUND
Glioblastoma often can relapse as mesenchymal (MES) tumors, indicating a phenotypic shift during clinical progression. Glioma spheres, when they gain MES phenotypes, develop dependence on AXL for their growth both in vitro and in vivo. The first-in-class orally bioavailable AXL kinase inhibitor bemcentinib has IC50 of 14 nM and is &gt; 100-fold selective for AXL over other kinases. Bemcentinib is currently under evaluation as a monotherapy and in combination with other treatments across various PhII trials in several oncology indications.

METHODS
This is an open-label, multicenter, intratumoral pharmacokinetic study of bemcentinib in patients with recurrent glioblastoma for whom a surgical resection is medically indicated. All subjects must have had histological confirmation of glioblastoma by either biopsy or resection that is progressive or recurrent following radiation therapy ± chemotherapy. Intratumoral drug levels were analyzed by LC/MS.

RESULTS
A planned analysis after the first 5 patients were enrolled with glioblastoma (4 IDH WT and 1 IDH-mutant), (3m, 2f, median age 57, KPS 80). Bemcentinib concentration in contrast enhancing brain tissue ranged from 3.1 to 43.0 uM with a geometric mean concentration of 11.1 uM (% CV, 132.1). The drug concentration in contrast enhancing tumor tissue exceeded the 1.0 uM threshold in all 5 patients, satisfying the criteria of the protocol to enroll an additional 15 patients into the surgical study. Total drug levels were approximately 2-fold greater in contrast enhancing tissue as compared to tissue from a non-enhancing region of the tumor (geometric mean, 5.8 uM; % CV, 187.7). The mean ratio of the drug concentration in brain tissue to plasma was 25.9 (% CV, 92.7) for contrast enhancing tissue and 13.4 (% CV, 126.8) for non-enhancing tissue.

CONCLUSIONS
Bemcentinib readily distributes in brain tumor tissue following oral administration. The study continues to complete accrual for the remaining 15 patients.
CTNI-14. EVALUATING METABOLIC ALTERATIONS IN PATIENTS WITH EGFR ACTIVATED RECURRENT GLIOBLASTOMA (RGBM) BY INHIBITING EGFR WITH OSIMERTINIB
Authors: Cloughesy Timothy , Ellingson Benjamin , Gafita Andrei , Chun Saewon , Filka Emese , Nghiemphu Phioanh , Lai Albert , Green Stacey , Tsang Jonathan , Jingwen Yao , Calais Jeremie , Sonni Ida , Li Gang , Nathanson David 
Published: November 2021

Abstract

BACKGROUND
EGFR activated GBM is highly metabolically active and effective targeting with EGFR TKis in human-tumor models rapidly attenuates glucose metabolism engaging apoptotic machinery. Rapid changes in glucose uptake using 18F-FDG-PET is an effective predictive biomarker of therapeutic response in these models. Clinical 18F-FDG-PET may allow investigators to obtain early readout on EGFR TKi in this patient population. We explore this approach using osimertinib in EGFRamp/p53wt rGBM.

METHODS
EGFRamp/p53wt rGBM patients were treated with oral osimertinib 240mg for three days followed by 160mg/day until progression. F18-FDG-PET scan was obtained as a double baseline, 24 hours apart, prior to dosing with osimertinib. Third scan was obtained after 3 doses of 240mg. Primary objective defines test-retest variance of tumor FDG uptake before osimertinib and to evaluate if osimertinib significantly decreases glucose utilization after three doses. Study-drug and funding provided by AstraZeneca.

RESULTS
12 pts were evaluated, 10 female, median age 57.5 years (44-61). Volumetric mRANO showed no responses, 6 SD, 5 PD, and one NE. Median PFS was 31 days, no patient achieved 6-month-PFS and median OS was 5.5 months. No new adverse event signal appeared. Double baseline PET SUV mean was 0.97 (normalized to whole cerebellum) with upward trend from first to second scan with mean percent change of 2.8 and 95% CI(0.7,5.1). Change in PET from 2nd to 3rd showed mean percent change -3.2 with 95% CI (-11.1,4.8). Preclinical models suggest 15-20% attenuation is needed to predict improved outcomes in patients treated with EGFR-TKi.

CONCLUSION
F18-FDG-PET has little variance with test-retest showing upward trend with second scan. Post osimertinib F18-FDG-PET shows limited attenuation of tumor FDG uptake. No clinical signal was seen in study. Deeper attenuation of FDG uptake may be needed to show clinical effect from EGFR inhibitors. F18-FDG-PET can be used to evaluate change in tumor glucose utilization.
CTNI-16. TROTABRESIB (CC-90010, BMS-986378), A REVERSIBLE, POTENT ORAL BROMODOMAIN AND EXTRATERMINAL INHIBITOR (BETi) IN PATIENTS WITH HIGH-GRADE GLIOMAS: A PHASE 1 OPEN-LABEL ‘WINDOW OF OPPORTUNITY’ STUDY
Authors: Vogelbaum Michael , Sepulveda Juan Manuel , Reardon David , Hanna Bishoy , Filvaroff Ellen , Aronchik Ida , Amoroso Barbara , Zuraek Marlene , Sanchez-Perez Tania , Mendez Cristina , Nikolova Zariana , Moreno Victor 
Published: November 2021

Abstract
Trotabresib is a potent, reversible oral BETi with antitumor activity in patients with advanced malignancies (Moreno et al. ESMO 2020. Abstract 5270). The CC-90010-GBM-001 study (NCT04047303) enrolled patients with progressive or recurrent astrocytoma or recurrent glioblastoma scheduled for salvage resection. Patients were treated with trotabresib 30 mg daily for 4 days before surgery, then trotabresib 45 mg daily 4 days on/24 days off after recovery. Primary objectives were trotabresib tumor tissue concentration and plasma pharmacokinetics (PK). Secondary and exploratory objectives included safety, antitumor activity, cerebrospinal fluid concentration, and pharmacodynamics (PD). Twenty patients were enrolled; blood PK, blood PD, and tumor PD data were available for 14, 12, and 11 patients, respectively. Geometric mean peak trotabresib plasma concentration on day 4 was 1.92 μM; median time to peak concentration was 1.5 hours. At the time of resection, geometric mean trotabresib concentrations in plasma and brain tumor tissue were 1.01 and 0.68 μM, respectively. Blood CCR1 mRNA was reduced ≥ 50% from baseline after dose 4. Blood HEXIM1 mRNA increased at 72–96 hours following first dose, and at the time of surgery the percentage increase was related to plasma trotabresib concentration. Tumor HEXIM1 RNA increased in 10 of 11 patients. Eighteen patients (90%) had ≥ 1 treatment-related adverse event (TRAE). Nine patients (45%) had grade 3/4 TRAEs, most frequently thrombocytopenia (5 patients [25%]). Only 1 patient had serious TRAEs (hemiparesis and lethargy). Two patients died of intracranial hemorrhage unrelated to study drug. Of 16 patients evaluable for antitumor response, 7 had stable disease per RANO criteria, with 3 ongoing beyond data cutoff at cycles 4–11. Median progression-free survival was 1.9 months (95% CI, 1.4–3.3). Overall, trotabresib showed good tumor tissue penetration, with PD signals of response, and was well tolerated. A study of trotabresib + temozolomide in first-line glioblastoma is ongoing (NCT04324840).