bluuebunny/crossref_metadata_2025_split huggingface dataset:
RADT-27. EFFECTIVENESS ANALYSIS OF RADIOTHERAPY FOR INTRACRANIAL RECURRENT EPENDYMOMA
Authors: Hu Qingjun , Lai Mingyao , Li Juan , Cai Linbo 
Published: November 2021

Abstract

OBJECTIVE
There is no standard treatment for recurrent ependymoma. This study aimed to investigated the role of radiotherapy in recurrent ependymoma.

METHODS
Retrospective analysis was performed on 49 cases of recurrent ependymoma diagnosed in Guangdong Sanjiu Brain Hospital from January 2008 to July 2020. Overall survival (OS) was calculated by Kaplan-Meier method and tested by Log-rank test. P &lt; 0.05 was considered statistically significant.

RESULTS
The median age was 7 years (range:1-57 yrs). Nineteen patients were with ependymoma WHO grade II while 30 were with grade III, respectively. Recurrence treatment: 14 cases received re-surgery, 23 cases received radiotherapy, among them 16 cases received re-radiotherapy. To May, 2021, the median follow-up time was 35 months (range 3-153). Median PFS time was 17 months after initial diagnosis, median PFS time was 8 months after treatment to recurrence disease, Median OS time is 39 months, and median OS time is 20 months after recurrence. The median survival time for recurrence was 48 months vs. 11 months (P =0.001) in the radiotherapy group vs. non-radiotherapy group,res; Re-radiotherapy combined with chemotherapy vs reradiotherapy alone (0.194); RRT combined with anti-angiogenesis therapy vs. RRT alone (0.688).

CONCLUSION
Radiotherapy can prolong the survival time of recurrent ependymoma, and concurrent therapy as chemotherapy or anti-angiogenesis therapy with RT does not seem to improve the prognosis. Therefore, radiotherapy can be used as the main treatment for recurrent ependymoma.
RADT-35. CHANGE IN HIPPOCAMPAL VOLUME AS A FUNCTION OF RADIATION DOSE: RESULTS FROM A PROSPECTIVE TRIAL WITH STANDARDIZED IMAGING AND MORPHOMETRIC EVALUATION
Authors: Hall Matthew , Odia Yazmin , Niazi Toba , Naidoo Reshma , Alamdari Golnar , Kotecha Rupesh , Tom Martin , Mohler Alexander , Wroe Andrew , Yu Jen , Von Werne Katherine , Gallardo Laura , Walters Rameen , Abrams Kevin , Altman Nolan , Medina Santiago , Chuong Michael , Mehta Minesh 
Published: November 2021

Abstract

PURPOSE/OBJECTIVES
MRIs in pediatric and adult brain tumor patients (Age&lt; 35) were prospectively collected at baseline and during follow-up to measure volumetric changes in multiple brain substructures with neurocognitive, laboratory, and quality-of-life assessments. In this planned interim analysis, we model early outcomes for change in hippocampal volume at 6 months following radiotherapy.

MATERIALS AND METHODS
As of 5/15/2021, 50 patients enrolled on this prospective study and 41 completed 6-month post-treatment assessments after fractionated intensity-modulated proton therapy. Left and right hippocampus volumes were independently measured on T1 sagittal precontrast MRI at baseline and 6-months after radiotherapy using both automated software and physician-delineated contours. The relationship between mean hippocampus dose and change in volume was assessed by Pearson’s correlation coefficient. A linear mixed-effects model was applied to evaluate other predictors associated with change in hippocampal volume, assuming random effects of subjects.

RESULTS
Mean hippocampus dose was strongly correlated with change in hippocampal volume at 6 months following radiotherapy (r=−0.727, 95% CI [-0.820,-0.596], p&lt; 0.001). Changes in hippocampal volumes over time were similar between software and physician contours. Hippocampal volume was significantly reduced for mean doses ≥10 Gy (mean Δ -10.8% ± 5.5%, p&lt; 0.001), while no significant volume change was observed with mean doses &lt; 10 Gy (mean Δ +0.7% ± 3.9%). In the mixed-effects model, only mean hippocampus dose was significantly associated with hippocampal volume change (p&lt; 0.001). The final model predicted a -3.4% change in hippocampal volume for every 10 Gy increase in mean dose.

CONCLUSIONS
Change in hippocampal volume was correlated with hippocampus mean dose at 6 months following radiotherapy. Future analyses will assess volume change in the hippocampus and other brain substructures over time as a function of radiation dose and correlate with measured neurocognitive and other effects.
CTIM-01. PHASE II TRIAL OF PEMBROLIZUMAB AND LENVATINIB FOR LEPTOMENINGEAL METASTASES
Authors: Wang Nancy , Gerstner Elizabeth , Cahill Daniel , Oh Kevin , Cahill Jennifer , Brastianos Priscilla 
Published: November 2021

Abstract
Leptomeningeal metastasis (LMD) is a late complication of cancer with poor prognosis and median survival of approximately 4-6 weeks without treatment. Whole brain radiation remains the mainstay of treatment, however it can cause significant neurocognitive sequelae and has not been shown to prolong overall survival. Thus, new treatment strategies are urgently needed to improve outcomes in patients with LMD. Results from recent Phase 2 studies of immune checkpoint inhibitors in LMD shows promising improvement in overall survival. Combining anti-VEGF therapy and immunotherapy may control symptoms due to inflammation and tumor-induced irritation, minimize steroid use, and promote improved efficacy of immunotherapy through modulation of the tumor immune microenvironment. We designed a multi-institutional, single-arm Phase 2 study of pembrolizumab in combination with lenvatinib in patients with LMD from any solid tumor. The primary objective is to estimate the overall survival rate at 6 months (OS6). A Simon two-stage design with a total sample size of 19 evaluable patients will be used to compare a null hypothesis of OS6 of 25% against an alternative hypothesis of 55%. Secondary objectives include assessing safety of pembrolizumab and lenvatinib in this patient population, systemic response rate, intracranial/intraspinal response rate, and progression-free survival. We will also explore clinician-reported neurologic outcomes and patient-reported quality of life and symptom burden. Blood, cerebrospinal fluid, and tissue biomarkers will be analyzed to determine predictors of response. Patients must be on minimal doses of steroids prior to study enrollment and cannot have received prior immune checkpoint inhibitor or anti-VEGF therapy. Response to treatment will be determined using RANO-BM for intracranial disease and RECIST 1.1 for systemic disease. Study accrual is anticipated over 12-24 months with anticipated total study duration of 30 months.
CTIM-06. CLINICAL EFFICACY AND BIOMARKER ASSESSMENT OF VT1021, A CD36/CD47 DUAL-TARGETING AGENT, IN RECURRENT GLIOBLASTOMA
Authors: Ahluwalia Manmeet , Battiste James , Bockorny Bruno , Bullock Andrea , Patel Manish , Wen Patrick , Shepard Dale , Vaickus Lou , Vincent Melanie , Chen Jian jenny , Wang Suming , Watnick Randolph , Crochiere Marsha , Cieslewicz Michael , Watnick Jing 
Published: November 2021

Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain malignancy in adults and recurs after treatment in &gt;90% of all patients. Prognosis of patients with recurrent GBM (rGBM) is poor with a median progression free survival of ~1.8 months and median overall survival of 8-10 months. VT1021, a cyclic peptide derived from prosaposin, induces the expression of thrombospondin-1 (TSP-1) in myeloid derived suppressor cells (MDSCs), which are heavily recruited to the tumor microenvironment. Following completion of the Phase 1 Dose Escalation study and determination of the RP2D, an expansion study was conducted in a heavily pretreated rGBM population. The results of the expansion study reveal that VT1021 is safe and well tolerated in rGBM. Pharmacodynamic response to VT1021 was observed by induction of TSP-1 in circulating MDSCs and in the tumor microenvironment. VT1021 demonstrated significant single agent activity. Among 22 evaluable GBM subjects, 3 had complete response (CR), 1 had partial response (PR), and 7 had stable disease (SD) with an average study duration of over 120 days. The overall disease control rate (DCR) was 50%. Among the 3 CR, 2 showed complete radiological regression of the target lesion, the third was found to have no evidence of disease upon pathological examination following surgery. Nine of the 19 (47%) evaluable subjects with available biopsy samples showed high expression levels of both CD36 AND CD47. Among these 9 subjects, 3 achieved CR, representing an overall response rate of 33.3%, with another 3 patients achieving SD for a DCR of 67%. In conclusion, VT1021 demonstrates promising single-agent clinical activity in rGBM, particularly in subjects with high expression levels of CD36 and CD47. Additional clinical studies have been planned to further investigate the efficacy of VT1021 in rGBM and other solid tumor indications.
CTIM-12. A PHASE 1 TRIAL OF IMMUNORADIOTHERAPY WITH THE IDO ENZYME INHIBITOR (BMS-986205) AND NIVOLUMAB IN PATIENTS WITH NEWLY DIAGNOSED MGMT PROMOTER UNMETHYLATED IDHwt GLIOBLASTOMA
Authors: Lukas Rimas , Sachdev Sean , Kumthekar Priya , Dixit Karan , Grimm Sean , Gondi Vinai , Sharp Laura , Lezon Ray , James David , Lesniak Maciej , Stupp Roger , Wainwright Derek 
Published: November 2021

Abstract

BACKGROUND
IDHwt glioblastoma with unmethylated MGMT gene promoter carries a poor prognosis. Preclinical studies have shown that combination of radiotherapy and dual immunotherapy with nivolumab and IDO inhibition significantly prolongs survival of mice with an orthotopic glioblastoma [Ladomersky, et al. CCR 2018;24(11):2559-2573]. In a clinical trial in patients with newly diagnosed glioblastoma with unmethylated MGMT we substituted temozolomide for dual immunotherapy combination.

METHODS
Phase 1 trial [NCT04047706] using a 3 + 3 dose-escalation design. All received standard radiotherapy (30 x 2 Gy) with addition of once daily oral BMS-986205 and intravenous nivolumab (240mg every 2 weeks) begining on day 1 of radiotherapy and continuing until disease progression or intolerance. BMS-986205 dosing was increased from 50 mg to 100 mg. DLT period encompasses 6 weeks of radiotherapy and the 4 subsequent weeks. Immunocorrelatives being conducted before and after treatment include mass spectrometry for tryptophan and kynurenine levels, immunohistochemistry of resected tumor, and RNA-sequencing and flow cytometric analysis of PBMCs.

RESULTS
Twelve patients were treated on 2 dose levels of BMS-986205 (50, 100 mg). Treatment-emergent toxicity was as expected for this population. Three (25%) treatment-related SAEs were reported. Dose limiting toxicity of grade 3 transaminase elevation was observed in 2 patients at the 100 mg dose level, while at lower doses of BMS-986205 no substantial alterations of liver enzymes was observed. No other relevant treatment related toxicity occured. Ongoing immunocorrelative profiling and preliminary outcome data (all patients minimal follow-up &gt;12 months) will be available at the time of the meeting.

CONCLUSIONS
Dose limiting toxicity of BMS-986205 in combination with nivolumab and radiotherapy is hepatic (reversible) transaminitis. The recommended dose for further investigation is 50 mg. Accrual is ongoing for the MGMT promoter methylated cohort using the same regimen without withholding temozolomide. A randomized phase 2/3 trial is approved within the NRG network.
CTIM-16. PHASE 2 STUDY OF PEMBROLIZUMAB PLUS TTFields PLUS TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED glioblastoma (2-THE-TOP)
Authors: Tran David , Ghinaseddin Ashley , Chen Dongjiang , Rahman Maryam 
Published: November 2021

Abstract

INTRODUCTION
Emerging data indicate that TTFields, the new anti-mitotic treatment for GBM, stimulate immunity via the type-1 interferon (T1IFN) pathway of STING and AIM2 inflammasomes. Thus, we hypothesize that TTFields synergize with immune checkpoint inhibitors to induce anti-tumor immunity in GBM.

METHODS
We conduct a phase 2 study combining pembrolizumab, TTFields and maintenance TMZ in 25 patients with newly diagnosed GBM (ndGBM). To distinguish immune effects of TTFields from pembrolizumab, TTFields is started at cycle 1 of TMZ and pembrolizumab (200mg Q3Wks) at cycle 2. The primary endpoint is PFS vs. the historical control of TTFields plus TMZ (JAMA/318:2306-2316). Secondary endpoints include toxicity, immune signature of TTFields vs. pembrolizumab by single-cell RNAseq of PBMCs, and OS.

RESULTS
As of 05/24/2021, 25 patients with a median age of 61 years were enrolled. Eight (32%) and 4 (16%) had biopsy only and partial resection, respectively. Eighteen (72%) had unmethylated MGMT and 3 (12%) had an IDH mutation. The median follow-up was 14.7 months. Twelve (48%) were progression-free, and 15 (60%) were alive. Of 19 patients with follow-up &gt;=9 months, the median PFS was &gt;=11.2 months vs. 6.7 months in the control. Six (24%) patients with measureable tumors achieved partial to complete response. The most common serious adverse events were thrombosis, seizure, and metabolic disturbances in 4 (16%), 3 (12%), and 2 (8%) patients, respectively. We sequenced 193,760 PBMCs in 12 patients before pembrolizumab and detected robust post-TTFields T cell activation in 11 of 12 patients via the T1IFN trajectory with a strong correlation with the TCRab clonal expansion Simpson index (Spearman coefficient r=-0.8, P=0.014). Importantly, we defined a T cell-based gene signature of TTFields effects on TCRab clonal expansion.

CONCLUSION
The triple combination is well tolerated and shows early evidence of efficacy in ndGBM patients. Survival and molecular data will be updated.
CTIM-27. LOCOREGIONAL B7-H3-SPECIFIC CAR T CELLS FOR CHILDREN AND YOUNG ADULTS WITH DIPG: INTERIM REPORT OF BRAINCHILD-03 ARM C
Authors: Vitanza Nicholas , Wilson Ashley , Yokoyama Jason , Johnson Adam , Gust Jule , Huang Wenjun , Albert Catherine , Pinto Navin , Foster Jessica , Orentas Rimas , Paulovich Amanda , Berens Michael , Gardner Rebecca , Jensen Michael , Park Julie 
Published: November 2021

Abstract
Following preclinical optimization of B7-H3-specific CAR T cells against pediatric brain tumor models, we opened BrainChild-03 (NCT04185038), a phase 1 clinical trial of repeatedly dosed, outpatient, locoregional B7-H3-specific CAR T cells for children with recurrent/refractory central nervous system (CNS) tumors or diffuse intrinsic pontine glioma (DIPG). Here, we report the interim findings from patients enrolled on Arm C, dedicated to DIPG. The primary endpoints are feasibility and safety, with secondary endpoints of disease response. We utilize second-generation CAR T cells with a 4-1BB costimulatory domain and a methotrexate-resistant human DHFR mutein (huDHFRFS; L22F,F31S), allowing for methotrexate selection. We do not deliver conditioning chemotherapy. The first three evaluable patients with DIPG all met feasibility for generating a balanced CD4:CD8 CAR T cell product, with 3.85x109 CAR T cells generated for S005, 4.29x109 for S008, and 2.45x109 for S012, allowing for greater than 6 months of biweekly dosing for each patient. All subjects were treated at Dose Level 1 (1x107 CAR T cells). S005 received 10 doses before clinical progression greater than 2 years from diagnosis, S008 has received 10 doses and continues on therapy with decreased tumor volume, and S012 has received 5 doses and continues on study with stable disease. There have been no dose limiting toxicities (DLT). 3/3 patients exhibited post infusion fever, headache, and elevated serum CRP but no evidence of cytokine release syndrome (CRS) or systemic CAR T cells. 0/3 patients required PICU admissions. In the cerebrospinal fluid (CSF), 2/3 patients have had elevations of cytokines such as CXCL10 and CCL2, as well as circulating CSF CAR T cells. Advanced serial patient CSF proteomic and transcriptomic profiling are underway. Ultimately, this report provides preliminary evidence that outpatient locoregional B7-H3 CAR T cells for children with DIPG may be feasible and tolerable.
CTIM-28. MDNA55, AN INTERLEUKIN-4 RECEPTOR TARGETED IMMUNOTHERAPY, FOR RECURRENT GBM DELIVERED BY CONVECTION ENHANCED DELIVERY (CED)
Authors: Sampson John , Achrol Achal Singh , Aghi Manish K , Bankiewiecz Krystof , Bexon Martin , Brem Steven , Brenner Andrew , Chandhasin Chandtip , Chowdhary Sajeel , Coello Melissa , Ellingson Benjamin , Floyd John , Han Seunggu , Kesari Santosh , Merchant Fahar , Merchant Nina , Randazzo Dina , Vogelbaum Michael , Vrionis Frank , Zabek Miroslaw , Butowski Nicholas 
Published: November 2021

Abstract

BACKGROUND
MDNA55 is an IL4R-targeted toxin in development for treatment of recurrent glioblastoma (rGBM). MDNA55 binds to IL4R expressed by tumor cells and non-malignant cells of the tumor microenvironment.

METHOD
MDNA55-05 was an open-label, single-arm study of MDNA55 delivered by CED as a single treatment in patients with 1st or 2nd recurrence following de novo GBM, IDH wild type status and not indicated for resection at relapse. Dose volumes (up to 60mL) and concentration of MDNA55 (1.5 to 9.0 μg/mL) were studied.

RESULTS
MDNA55 showed an acceptable safety profile at all doses tested. Median OS (mOS) amongst all subjects was 11.9 months, OS-24 was 20%, and PFS-12 was 27%. Among subjects expressing high levels of IL4R (irrespective of MDNA55 dose) and low levels of IL4R expression administered high dose (≥ 180μg) of MDNA55 (IL4Rhi + IL4Rlo/hd), mOS further improved to 14.0 months with OS-24 of 20%. Unmethylated MGMT promoter status did not affect MDNA55 treatment outcomes. In the IL4Rhi + IL4Rlo/hd population (N=17), mOS was 14.9 months with OS-24 of 22%. Following treatment with high concentrations of MDNA55 (6.0 or 9.0 μg/mL), transient (median of 3 cycles) low dose Avastin (5mg/kg q2w or 7.5mg/kg q3w) was used for symptom control and steroid sparring. Among these subjects, mOS amongst all comers (N=9) and the IL4Rhi + IL4Rlo/hd group (N=8) increased to 21.8 and 18.6 months with OS-24 of 44% and 38%, respectively.

CONCLUSIONS
MDNA55 shows potential to benefit all rGBM patients treated at high dose irrespective of IL4R expression. In the 1:1 randomized Phase 3 trial, the study will enrol two-thirds of subjects in the SOC arm from a matched external control arm. Unlike conventional RCTs, the hybrid design sets a new precedent for GBM trials, allowing robust OS analysis while significantly reducing the number of subjects randomized to SOC arm.
CTNI-17. A PHASE 1 WITH DOSE EXPANSION/PHASE 2 STUDY OF SELINEXOR IN COMBINATION WITH STANDARD OF CARE THERAPY FOR NEWLY DIAGNOSED OR RECURRENT GLIOBLASTOMA
Authors: Odia Yazmin , Wen Patrick , Mehta Minesh , Colman Howard , Dunbar Erin , Butowski Nicholas , Harrison Rebecca , Schulder Michael , Boockvar John , Chow Frances , Kumthekar Priya , Mason Warren , Venur Vyshak , Plotkin Scott , Lassman Andrew , Duic Paul , Tamir Sharon , Li Kai , Liu Yang , Mundy Gregory , Damestani Yasaman , Sbar Eric , Shah Jatin , Shacham Sharon , Goldlust Samuel 
Published: November 2021

Abstract

BACKGROUND
Glioblastoma (GBM) is the most common and aggressive primary brain tumor with median overall survival of 15 months and 5-7 months for patients with newly diagnosed or recurrent disease (nGBM or rGBM), respectively. Selinexor is a first-in-class, oral, selective inhibitor of nuclear export which blocks exportin 1 (XPO1), forcing the nuclear retention and reactivation of tumor suppressor proteins, ultimately causing cancer cell death. Increased XPO1 expression in gliomas is associated with higher pathological grade and poorer prognosis. Consistent with these data, selinexor inhibited tumor growth and prolonged survival in an animal model of GBM. Importantly, selinexor showed encouraging intra-tumoral penetration and single-agent efficacy in rGBM (KING study). The current trial tests the hypothesis that adding selinexor to standard therapy will improve clinical outcomes for patients with nGBM or rGBM.

METHODS
To facilitate the successful development of new therapies, consensus recommendations are to use biomarker enrichment and flexible design that allows expansion of promising cohorts. Accordingly, this phase 1a dose finding study is followed by a phase 1b dose expansion (and ultimately by a 1:1 randomized phase 2 efficacy exploration trial) to independently evaluate: radiation + selinexor in nGBM with unmethylated MGMT promoter (Arm A), radiation + temozolomide + selinexor for nGBM with methylated MGMT promoter (Arm B), and lomustine + selinexor in rGBM (Arm C). Bevacizumab or TTField + selinexor in rGBM (Arms D & E, respectively) are being considered. The Phase 1a primary endpoint is maximum tolerated dose/recommended phase 2 dose. The phase 1b primary endpoint is PFS at 3 months against historic controls. The phase 1b dose expansion is included to evaluate preliminary efficacy before launching into a randomized phase 2 trial. Patient quality of life during the trial will be objectively measured using digital devices (e.g. smartwatch/customized smartphone app). We are currently enrolling patients nationwide. Clinical Trial Registration number: NCT04421378.
CTNI-36. SAFETY OF ONC201 ADMINISTERED TWO CONSECUTIVE DAYS PER WEEK IN PEDIATRIC H3 K27M-MUTANT GLIOMA PATIENTS
Authors: Gardner Sharon , Koschmann Carl , Tarapore Rohinton , Allen Jeffrey , Zaky Wafik , Odia Yazmin , Hall Matthew , Daghistani Doured , Khatib Ziad , Aguilera Dolly , MacDonald Tobey , de Blank Peter , McGovern Susan , Mueller Sabine , Kline Cassie , Vitanza Nicholas , Allen Joshua , Khatua Soumen 
Published: November 2021

Abstract
ONC201, an anti-cancer DRD2 antagonist and ClpP agonist, is in Phase II trials for adult H3 K27M-mutant diffuse midline gliomas. The recommended phase 2 dose (RP2D) of 625mg ONC201 once a week has been established as a biologically active dose that is well tolerated in adult and pediatric populations. Radiographic regressions with single agent ONC201 have been reported in recurrent H3 K27M-mutant glioma patients. In another study, twice/week dosing was explored in adult patients and deemed to be safe (no DLTs observed). This warranted exploration of twice/week dosing in pediatric patients and will be discussed in this presentation. This multi-arm, dose-escalation and dose-expansion trial (ONC014; NCT03416530) determined the pediatric RP2D of ONC201 administered once per week and twice per week on two consecutive days. ONC201 was orally administered and scaled by body weight. Dose escalation was performed by a 3 + 3 design beginning with two 125mg capsules less than the adult RP2D equivalent. Twelve children (8 females; 4 males) with H3 K27M-mutant gliomas (pons: 8; thalamus: 2; spinal cord: 2) aged 4-19 years have been treated post-radiation: 3 at dose level -1; 3 at dose level 1; 6 as part of the dose expansion cohort on dose level 2. Median KPS was 90 (range 70-100). One treatment cycle was 21 days (6 doses), which also defined the DLT window. Patients were on-treatment for a median length of 4 cycles (range: 2-11). Twice weekly dosing of ONC201 was tolerated well, as observed with weekly dosing, with no instance of DLT. A total of 4 SAEs were reported, none of which were related to the study drug. The most common AEs (regardless of relatedness) included headache, facial nerve disorder, abducens nerve disorder, nausea, fatigue and ataxia. Additional safety data, PK, and clinical outcomes from this arm will be reported.