bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTIM-12. A PHASE I CLINICAL TRIAL ON THE INTRACRANIAL ADMINISTRATION OF INCREASING DOSES OF IPILIMUMAB PLUS FIXED DOSE NIVOLUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA (RGB)
Authors: Geens Wietse , Schwarze Julia Katharina , Tijtgat Jens , Lescrauwaet Louise , Tuyaerts Sandra , Geeraerts Xenia , Stevens Latoya , Vanbinst Anne-Marie , Everaert Hendrik , Bruneau Michaël , Duerinck Johnny , Neyns Bart 
Published: November 2022

Abstract

BACKGROUND
Intra-operative intracerebral (iCE) administration of ipilimumab (IPI) and nivolumab (NIVO) after resection of rGB is safe and resulted in encouraging survival (NCT03233152J; Duerinck et al. JITC 2021).

METHODS
Eligible patients (pts) underwent a maximal safe resection followed by iCE administration of 5 mg IPI plus 10 mg NIVO and implantation of an Ommaya reservoir through which NIVO (10 mg) and IPI (cohort defined doses of 1-, 5- and 10 mg of IPI) were administered intracavitary (iCA) in combination with NIVO (10 mg) intravenously pre- and postoperatively and Q2w thereafter for up to 24w.

RESULTS
20 pts (13 male; median age 58y) were enrolled. One patient was excluded due to an intra-operatively diagnosed epidural bacterial infection. Respectively 4 pts were treated at the 1-, 4 pts at the 5-, and 11 pts at the 10 mg iCA IPI dose level. Median number and range of postoperative iCA administrations of IPI/NIVO was 2 (0-4) at the 1 mg dose level, 5 (1-10) at the 5 mg dose level, and pending for the 10 mg dose level. Most important treatment related adverse events were symptomatic aseptic neutrophilic pleocytosis (3 pts, all treated at the 10 mg IPI dose level), subacute cerebral edema necessitating corticosteroid treatment (5 pts), and bacterial colonization of the Ommaya reservoir (3 pts). There were no G5 AE. Nine pts have progressed and 4 pts died from progressive disease. Molecular-genetic characterization of rGB tissues, analysis of cellular and cytokine content, and NIVO/IPI concentrations in CSV samples are ongoing.

CONCLUSION
Repeated iCA administration of 10 mg NIVO plus 10 mg IPI resulted in treatment limiting aseptic neutrophilic pleocytosis. Safety of the presumed MTD of repeated 10 mg NIVO plus 5 mg IPI iCA will be further investigated.
CTIM-25. NEOADJUVANT ANTI-PD1 IMMUNOTHERAPY FOR SURGICALLY ACCESSIBLE RECURRENT GLIOBLASTOMA: CLINICAL AND MOLECULAR OUTCOMES OF A STAGE 2 SINGLE-ARM EXPANSION COHORT
Authors: Ricardo McFaline-Figueroa J , Prins Robert , Qiao Yu , Sun Lu , Li Gang , Kim Jiyoon , Lee Eudocia , Nayak Lakshmi , Chukwueke Ugonma , Beroukhim Rameen , Batchelor Tracy , Chiocca E Antonio , Doherty Lisa , Stefanik Jennifer , Partridge Kathryn , Spearman Amanda , Lavallee Maria , Myers Alexa , Laforest-Roys Corey , Garcia Rachel Fox , Bi Wenya Linda , Arnaout Omar , Peruzzi Pierpaolo , Cosgrove G Rees , Ligon Keith , Arrillaga-Romany Isabel , Clarke Jennifer , Reardon David A , Cloughesy Timothy , Wen Patrick Y 
Published: November 2022

Abstract
Glioblastoma is immunologically “cold”, with little clinical response to single-agent immune-checkpoint inhibitors (ICI). Our previous randomized study of neoadjuvant and adjuvant pembrolizumab versus adjuvant pembrolizumab in recurrent glioblastoma identified a molecular signature for ICI and suggested that neoadjuvant pembrolizumab improved survival (PMID30742122). We extended these original findings with a single-arm expansion cohort of glioblastoma patients at first or second relapse undergoing surgical resection for recurrent disease. Eligibility was identical to the original study. Patients receiving &gt; 4mg dexamethasone, or with prior immunotherapy or anti-angiogenic therapy were excluded. The primary objective was to determine the effect of neoadjuvant pembrolizumab on cell cycle/cancer proliferation genes. Secondary objectives were PFS-6 and OS. Twenty-five patients received neoadjuvant pembrolizumab followed by tumor resection and adjuvant pembrolizumab until progression or unacceptable toxicity. The median age of participants was 60 years and median KPS was 90. Ninety-six percent of tumors were IDH wild-type and 48% were MGMT promoter methylated. Neoadjuvant pembrolizumab continued to induce alterations in the tumor microenvironment (T-cell/IFN upregulation, cell cycle downregulation; molecular responders (MR)), but the proportion of MR in this trial was 36% compared with 70% in the original treatment cohort. Median OS was 6.8 months. There were no CTCAE grade 4-5 AEs attributable to pembrolizumab. Further analysis of prognostic differences between stage 1 and 2 subjects is underway, as are additional immune and genotypic correlates to further define molecular changes induced by pembrolizumab. Anti-PD1 monotherapy triggers an intra-tumoral genetic signature associated with interferon-γ response and suppression of cell cycle/cancer proliferation in recurrent glioblastoma, though does not extend OS. This surgical window-of-opportunity paradigm allows for attribution of molecular effects to single agents. Future work will evaluate the differences in patient population, tumor characteristics, and address additional immune checkpoints and/or signaling pathways that can be targeted to augment the effectiveness of anti-PD1 in glioblastoma.
CTIM-32. FIRST-IN-CHILDREN PHASE 1 TRIAL OF INDOXIMOD-BASED CHEMO-IMMUNOTHERAPY FOR PATIENTS WITH PEDIATRIC BRAIN TUMORS: ANALYSIS OF SAFETY, TOLERABILITY, AND 5-YEAR OUTCOME
Authors: Johnson Theodore , Pacholczyk Rafal , Aguilera Dolly , Al-Basheer Ahmad , Bajaj Manish , Bandopadhayay Pratiti , Berrong Zuzana , Bouffet Eric , Castellino Robert , Dorris Kathleen , Eaton Bree , Esiashvili Natia , Foreman Nicholas , Fridlyand Diana , Giller Cole , Heger Ian , Kadom Nadja , Kennedy Eugene , Manoharan Neevika , Martin William , McDonough Colleen , Parker Rebecca , Ramaswamy Vijay , Ring Eric , Rojiani Amyn , Sadek Ramses , Smith Amy , Smith Chris , Vaizer Rachel , Yeo Kee Kiat , MacDonald Tobey , Munn David 
Published: November 2022

Abstract

BACKGROUND
Recurrent brain tumors are the leading cause of cancer death in children. We conducted a first-in-children, two-institution, Phase 1 open-label dose-confirmation study using a 3 + 3 design, with expansion cohorts, to determine the recommended pediatric dose of the IDO pathway-inhibitor indoximod (NCT02502708). DESIGN/

METHODS
Eligible patients were 3-22 years old with either recurrent malignant brain tumor or newly-diagnosed diffuse intrinsic pontine glioma (DIPG). Palliative radiation, surgery or dexamethasone were allowed as needed for patient management. Separate dose-finding arms were performed for indoximod plus temozolomide (200 mg/m2/day orally for 5 days of each 28-day cycle) and for indoximod plus conformal radiation (in patients for whom re-irradiation was planned as standard-of-care). At progression, patients who were otherwise clinically stable were offered crossover to indoximod plus a second-line chemotherapy regimen (cyclophosphamide 2.5 mg/kg/day orally and etoposide 50 mg/m2/day orally for 21 days of each 28-day cycle).

RESULTS
Between December 2015 and January 2019, the study enrolled 81 brain tumor patients, including newly-diagnosed DIPG (n = 13) or recurrent ependymoma (n = 27), glioblastoma/high-grade glioma (n = 19), medulloblastoma (n = 13), or other CNS tumors ( n= 9). Median follow-up was 52 months (range 39-77 months). No dose-limiting toxicities were observed, and the pediatric indoximod dose was determined (19.2 mg/kg/dose, given twice daily). Indoximod was well tolerated and did not affect the ability to deliver chemotherapy or radiation as planned. Median overall survival was 13.6 months (n = 81). Median overall survival was 34.7 months for the subset of patients who continued indoximod with second-line chemotherapy after progression on indoximod plus temozolomide (n = 18).

CONCLUSIONS
Indoximod was well tolerated and could be combined with a variety of standard treatments for pediatric brain tumors. Preliminary anti-tumor activity and overall survival suggest that indoximod with standard therapy should be further evaluated in pediatric brain tumors, and potentially other pediatric solid tumors.
CTIM-33. SEXUAL DIMORPHISM OF HUMAN IMMUNE SYSTEM PREDICTS CLINICAL OUTCOMES IN GLIOBLASTOMA IMMUNOTHERAPY: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Shireman Jack , Ammanuel Simon , Eickhoff Jens , Dey Mahua 
Published: November 2022

Abstract
Biological differences based on sex have been documented throughout scientific literature. Glioblastoma, the most common primary malignant brain tumor in adults, has a male sex incidence bias, however, no clinical trial data examining differential effects of treatment between sexes currently exist. We analyzed genomic data, as well as clinical trials, to delineate the effect of sex on the immune system and glioblastoma outcome following immunotherapy. We found that, in general females possess enriched immunological signatures on gene set enrichment analysis, that also stratified patient survival when delineated by sex. Female glioblastoma patients treated with immunotherapy had a statistically significant survival advantage at the 1-year compared to males (RR = 1.15; p = 0.0241). This effect was even more pronounced in vaccine-based immunotherapy, (RR = 1.29; p = 0.0158). Our study shows a meaningful difference in the immunobiology between males and females that also influences overall response to immunotherapy in the setting of glioblastoma. Our study adds to a growing body of literature examining sex differences in male and female immunology. We demonstrate both using large scale omic data sets, as well as clinical trials, that female sexually dimorphic genes are tied to immunological responses, and that females have better outcomes during GBM immunotherapy treatments. This data is critical to better inform treatment practices and further crystalizes the need for balanced trial design and prospective reporting of sex as a variable across all GBM clinical trials.
CTNI-28. SYSTEMATIC REVIEW OF PHASE III TRIALS IN NEWLY DIAGNOSED GLIOBLASTOMA 2005-2021
Authors: Oster Christoph , Lazaridis Lazaros , Feldheim Jonas , Schmidt Teresa , Kleinschnitz Christoph , Kebir Sied , Glas Martin 
Published: November 2022

Abstract

BACKGROUND
Despite a plethora of studies since the EORTC/NCIC trial in 2005, glioblastoma (GBM) prognosis remains poor. We here identify and compare glioblastoma phase III trials in terms of efficacy and baseline characteristics in an attempt to summarize the experience of the past 16 years.

METHODS
A systematic literature search using PubMed and ClinicalTrials.gov was conducted to provide an overview of clinically relevant GBM phase III trials (years 2005-2021) of adult patients younger than 70 years of age. Search results were screened according to predefined inclusion criteria and either excluded or included in further analysis on study design, baseline characteristics, and survival results.

RESULTS
Eleven trials from the literature and clinical trial database fulfilled the search criteria. Among these trials, a total of three GBM phase III trials reported overall survival (OS) benefit, including the EORTC/NCIC study (NCT00006353), EF-14 (NCT00916409) and CeTeG/NOA09 (NCT01149109). All three studies demonstrate similar hazard ratios, which translate into risk reduction of about 40%. Furthermore, low toxicity profile and mostly preserved quality of life were attributed to the treatments tested. Looking at the study designs, eight out of eleven trials were open label randomized trials, including all of the positive ones, and only three negative trials employed treatment blinding and a placebo control. Canonical baseline characteristics (extent of resection, age, gender, MGMT promoter methylation status) did not significantly differ between positive and negative trials. IDH mutation status was analyzed in only two trials, each showing a small percentage of IDH-mutant tumors only.

CONCLUSION
This analysis on GBM phase III trials conducted between 2005 and 2021 revealed that the majority of trials did not show a significant improvement in overall survival. CeTeG/NOA-09 and EF-14 are the only two studies with positive overall survival outcome since the EORTC/NCIC trial in 2005.
CTNI-48. TRIAL UPDATE -RESULTS OF A PHASE I WINDOW OF OPPORTUNITY TRIAL EVALUATING A FIRST-IN-CLASS CD29 INHIBITOR, OS2966, IN RECURRENT HIGH-GRADE GLIOMA
Authors: Liu James , Carbonell Anne-Marie , Nwagwu Chibueze , Immidisetti Amanda , Vogelbaum Michael 
Published: November 2022

Abstract

BACKGROUND
OS2966 is a first-in-class, humanized, and deimmunized anti-CD29 (β1integrin) monoclonal antibody. CD29 is a mechanosignaling receptor prominently upregulated in glioblastoma. Preclinical studies in mice and non-human primates have demonstrated safety and encouraging efficacy. A phase I clinical trial was therefore initiated to evaluate the safety and feasibility of delivering OS2966 directly to the site of disease via convection-enhanced delivery (CED) in recurrent high-grade glioma patients.

METHODS
This study employs a 2-part design: In part 1, patients undergo stereotactic tumor biopsy followed by placement of a CED catheter(s) for delivery of OS2966 to the bulk contrast-enhancing tumor. Subsequently, in part 2, patients undergo a clinically-indicated tumor resection followed by placement of CED catheter(s) and delivery of OS2966 to the surrounding tumor-infiltrated brain. Co-convection of gadolinium enables real-time monitoring of therapeutic delivery. A concentration-based accelerated titration design is utilized for dose escalation. Given availability of pre and post-infusion samples, pharmacodynamic data will be analyzed to explore mechanism of action of OS2966.

RESULTS
Four patients have completed treatment in both study parts. No dose-limiting toxicity or adverse events related to treatment with OS2966 or CED catheter placement have been reported at the first 3 dose levels (ie, doses up to 0.6 mg/mL). For the four patients treated an average of 4.2 mL and 3.2 mL were infused in study parts 1 and 2 respectively. The Vd/Vi ratio ranged from 0.6 to 1.6 in part 1, and from 2.0 to 4.3 in Study Part 2. Analysis of tissue samples collected during the trial has demonstrated decreased VEGF expression post-treatment, with preinfusion samples showing &gt; 50% VEGF expression and post-infusion samples showing 10% expression. Additional pharmacodynamic analysis via tissue-level biomarkers is ongoing and will be presented.

CONCLUSION
Initial data demonstrate the safety and feasibility of direct intracranial delivery of OS2966.
CTNI-56. A MULTI-INSTITUTIONAL RETROSPECTIVE SERIES OF ADULT-ONSET MEDULLOBLASTOMA
Authors: Bonm Alipi , Rutenberg Michael , Therkelsen Kate , Ruiz Amber , McGranahan Tresa , Cimino Patrick , Nagpal Seema , Taylor Lynne 
Published: November 2022

Abstract
Adult-onset medulloblastoma is a rare tumor for which limited data exists. Current treatment is based on data from childhood medulloblastoma. We present a retrospective cohort of 130 consecutive patients age ≥ 18 years and treated at the University of Washington (N = 61), University of Florida (N = 50), and Stanford University (N = 19), from 2000-2021. Median duration of follow-up was 57.3 months. Patients were 57.7% male (75/130), with median age at diagnosis of 29 years. 5 and 10-year overall survival were 78.9% and 67.6% and no recurrence was seen beyond 10 years. 31/130 (23.8%) patients had Chang M1 or greater disease and molecular typing was available for 41/130 patients. There was no improvement in progression-free survival (PFS) or overall survival (OS) either in patients who received proton therapy or those who received concurrent vincristine. There was a trend favoring longer OS in patients receiving radiotherapy within 6 weeks of surgery. A trend towards shorter OS in patients receiving a higher craniospinal radiation dose ( &gt; 30Gy) likely reflected accurate clinical risk stratification. There was no improvement in OS or PFS for adjuvant chemotherapy overall, but patients receiving ≥ 5 cycles had improved PFS (HR 2.10, 95% CI = 1.19 - 3.90, p = 0.038) and a trend to improved OS (HR 2.07, 95%CI = 0.81-5.25, p = 0.125). After first progression, median OS was 20.7 months and both 5 and 10-year survival were 24.8%. We conclude that surveillance past 10 years may be unnecessary and that 1 in 4 patients achieve long-term survival after first relapse. Within the confines of a retrospective study, these data suggest equivalence between proton and photon radiotherapy, no benefit to concurrent vincristine, and that at least 5 cycles of adjuvant chemotherapy are required to delay progression.
CTNI-64. FOCUSED ULTRASOUND MEDIATED BLOOD-BRAIN BARRIER PENETRANCE TO ENABLE CELL-FREE DNA (CFDNA) AS A LIQUID BIOPSY IN RECURRENT PRIMARY BRAIN TUMORS
Authors: Miller Alexandra , Ramamurthy Bhaskar , Pike Luke , Keralapura Mallika , Hofius Jonathan , Marshall Jack , Jones Marvin , Lee Chi-Yin , Stember Joseph , Brennan Cameron , Kaley Thomas , Dittamore Ryan , Mellinghoff Ingo 
Published: November 2022

Abstract
The WHO recommends molecular characterization of CNS tumors. (Louis et al., 2021, 2016). However, many patients at diagnosis and recurrence, do not have tissue accessible for genomics. Blood-based liquid biopsy tests, provide a non-invasive means to obtain genomic data. Liquid biopsy tests are widely adopted to avoid side effects related to invasive biopsies in other solid tumors. However, for primary brain tumors, most patients have cfDNA concentrations below the Limit-of-Detection (LOD) of the tests. The primary contributor to low yield is the blood-brain barrier (BBB) which prevents free passage of tumor analytes into the circulatory system. BBB opening mediated by Focused Ultrasound (FUS) oscillation of microbubbles (MB) has led to an increase of tumor-derived circulating biomarkers in pre-clinical models and in human GBM (Zhu et al 2018, Meng et al 2021). Cordance Medical is developing a non-invasive, portable FUS platform that can enable clinic-based BBB opening treatments. The Cordance device utilizes three transducer types, a Type 1 transducer for non-invasive BBB opening localization obtains Doppler images of the Circle-of-Willis through the temporal lobe. The Doppler images align to the existing MRI using CoW as the fiducial. An array of Type 2 transducers for BBB opening to generate sufficient acoustic pressure to safely oscillate MBs to open the BBB. Finally, Type 3 transducers for safety monitoring receive echo signals from the MBs. Signals are analyzed for harmonic content which enables safety monitoring. The primary endpoint, we will be examining the Cordance platform's ability to increase the concentration of circulating biomarkers following a safe BBB opening. We will recruit patients with recurrent GBM. Patients will receive a baseline blood draw, a BBB opening treatment with the Cordance device, followed by a blood draw after the treatment. Liquid biopsy tests to be examined include the MSK ACCESS test and tumor-informed ddPCR MRD test.
DNAR-06. LOSS OF HISTONE H3 THREONINE 45 PHOSPHORYLATION DECREASES H3K36ME3 TO ABROGATE THE RADIATION-INDUCED DNA DAMAGE IN GLIOBLASTOMA MULTIFORME
Authors: Parwani Kiran , Spangle Jennifer , McSwain Leon , Javadi Ramona Haji Seyed , Kenney Anna , Yu David 
Published: November 2022

Abstract
Glioblastoma multiforme (GBM) is the most common and fatal adult brain tumour. As radioresistance is a common occurrence and contributes to poor patient prognosis, exploiting the mechanistic basis of GBM radioresistance to develop new therapeutic approaches remains an unmet clinical need. Chromatin post-translational modifications (PTMs) can augment cancer radioresistance. Several chromatin PTMs are regulated by PI3K/AKT, which is frequently hyperactivated in GBM. Previous research demonstrated that the PI3K effector AKT phosphorylates histone H3 at threonine 45 (pH3T45) in response to DNA damage. To genetically dissect the function of H3T45 phosphorylation in the DNA damage response, we engineered the PI3K pathway-activated U87MG GBM cell line to stably overexpress wildtype H3, or a phospho-null H3T45A mutant. We show that in both the presence and absence of irradiation, cells harbouring the phospho-null H3T45A mutant decreases H3K36me3 on free and nucleosome-incorporated histones, which may suggest a deficiency in DNA repair protein recruitment. By surveying irradiation-induced 53BP1 foci formation, we demonstrate that loss of pH3T45 compromises damage repair through NHEJ by delaying the onset of repair signaling. We also observe a defect in DNA damage resolution, which enhances apoptosis to reduce cell clonogenicity and proliferative capacity. Irradiation does not further reduce clonogenicity and proliferation in the phospho-null H3T45A-expressing cells. Taken together, these data suggest a critical function for PI3K-directed H3T45 phosphorylation in DNA damage repair and that loss of pH3T45 may contribute to GBM radioresistance. We anticipate that further characterization of this phosphorylation event will inform the understanding of GBM radioresistance and may suggest novel therapeutic strategies.
DDEL-01. ANIMAL STUDIES WITH A NEW CNS DRUG DELIVERY DEVICE TO EFFECTIVELY TREAT LEPTOMENINGEAL CARCINOMATOSIS PATIENTS
Authors: Kumthekar Priya , Benatti Hector , Taghian Toloo , Gormley William B , Nagpal Seema , Baker William C , Patel Rajan , Brown Emma , Glicksman Marcie , Gray-Edwards Heather 
Published: November 2022

Abstract

Background
Appropriate drug distribution is needed for effective treatment of brain metastases and leptomeningeal carcinomatosis. Lack of proper drug bioavailability in the CNS contributes to the poor outcome in these patients. EnClear Therapies has developed a device delivering intrathecal therapeutics utilizing the active control of CSF flow through an external pump. Herein, we look at intrathecal drug delivery of methotrexate with EnClear’s system and its impact of drug concentration in sheep and non-human primates.

METHODS
The EnClear device utilizes two implantable catheters (intracranial in the ventricular system and lumbar thecal sac) and an extracorporeal pump that controls the speed and direction of CSF flow. Software monitors the output from sensor arrays for pressure, respiration, and heart rate. Gadolinium and MRI were used to determine the CSF flow characteristics. Administration of Methotrexate via the EnClear system was compared to current two standards of delivery, intracerebroventricular or lumbar intrathecal administration. Methotrexate levels were measured with Liquid Chromatography/Mass Spectrometry in CSF, blood, and multiple CNS and peripheral tissues.

RESULTS
There was a two-fold increase in methotrexate levels in multiple regions of the brain including deeper brain structures including the striatum using the EnClear's system, compared to traditional lumbar intrathecal and intracerebroventricular delivery. Higher peak levels of methotrexate were reached in the CSF with the use of EnClear’s system, with simultaneous reduction in the peripheral nerves and systemic tissues – a potential source of toxicity.

Conclusions
In large animal studies, the EnClear device has for the first time, demonstrated increased brain parenchymal drug levels via intrathecal delivery. In addition to the drug parenchyma, drug delivery with this novel device has shown improved distribution throughout CNS and leptomeninges as compared to traditional intrathecal drug delivery and decreased peripheral distribution.