bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-50. A RANDOMIZED PHASE 2 TRIAL OF CEDIRANIB/OLAPARIB VERSUS BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA: UPDATED RESULTS
Authors: Hsieh Annie , Gerstner Elizabeth , Sahebjam Solmaz , Piccioni David , Campian Jian , Drappatz Jan , Aiken Robert , Lee Eudocia , Welch Mary , Becker Kevin , Williams Mickey , Karlovich Christopher , Muzikansky Alona , Giglio Pierre , Ivy Percy , Batchelor Tracy , Arrillaga-Romany Isabel 
Published: November 2022

Abstract

PURPOSE
Hypoxia from inhibition of angiogenesis reduces DNA repair capacity. Targeting homologous recombination pathway also has anti-angiogenic effects. To examine the synergistic effects of disrupting DNA repair pathways and angiogenesis in glioblastoma, we combine cediranib (ced), a pan vascular endothelial growth factor (VEGF) receptor inhibitor with olaparib (ola), a poly-ADP ribose polymerase (PARP) inhibitor compared with bevacizumab (bev), a VEGF-A inhibitor alone. To identify potential biomarkers predicting response to treatments, we also perform whole exome sequencing on archival tissues.

METHODS
Bevacizumab-naïve adult patients with first or second recurrence of glioblastoma after radiation and temozolomide were randomly assigned to cediranib (30mg PO daily)/olaparib (200mg PO twice daily) or bevacizumab (10mg/kg IV every 2 weeks). The primary end point was progression-free survival (PFS) at 6 months. The secondary end points included safety and overall survival (OS). Whole exome sequencing of formalin-fixed paraffin embedded archival tissue from 23 patients was performed.

RESULTS
We are presenting the final data from this trial. Between December 2017 and November 2018, a total 70 adult patients with recurrent glioblastoma were randomly assigned to receive ced/ola (n = 35) or bev (n = 35). With a data cut off on 5/30/2022, median PFS was 118 days and 92 days in ced/ola and bev groups, respectively (hazard ratio, 1.099, 95% CI 0.6-2, p = 0.76). Median overall survival was 269.5 days and 192 days in ced/ola and bev groups, respectively (hazard ratio, 0.6892, 95% CI 0.39-1.2, p = 0.2). Whole exome sequencing was performed in total 23 patients (24 samples), 14 patients in the ced/ola group and 9 patients in the bev group.

CONCLUSION
No significant survival benefit was observed in patients with recurrent glioblastoma treated with ced/ola compared to patients treated with bev monotherapy. Potential biomarkers predicting response to treatment identified from the whole exome sequencing on archival tissues will be presented.
CTNI-51. FEASIBILITY AND SAFETY OF NEUROSURGICAL RESECTION AND INTRA-OPERATIVE RADIATION THERAPY USING THE XOFT AXXENT ELECTRONIC BRACHYTHERAPY SYSTEM AND BEVACIZUMAB IN RECURRENT GLIOBLASTOMA
Authors: Wagle Naveed , Barkhoudarian Garni , Chaiken Lisa , Wollman Robert , Sharma Akanksha , Carrillo Jose , Nguyen Minh , Truong Judy , Chow Jared , Chacon Emma , Kesari Santosh 
Published: November 2022

Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor. External beam radiation therapy (EBRT) is widely recognized as an effective treatment for primary GBM. EBRT applied after GBM resection is associated with an increase in overall survival. Beyond upfront therapy with radiation and temozolomide chemotherapy, there is no standard therapy that has been proven effective. Re-irradiation with ERBT is minimally effective and with significant comorbidities. Our study uses IORT at the time of re-resection in patients who have recurrent, operable GBM after failure of who received primary EBRT and temozolamide in their first course of treatment. IORT allows the delivery of a large effective radiation dose applied directly to the tumor bed at the time of resection. This affords direct radiation to be delivered to the micro- and macroscopic tumor remnants in the vicinity of the resection cavity immediately following gross resection. In contrast, the more distant, surrounding brain tissue does not receive high radiation exposure. This Phase II study continues to accrue subjects with the primary endpoint of overall survival and several secondary endpoints that includes progression free survival, quality of life, and adverse events/safety. To date, five patients have been treated on this protocol. The technical feasibility and safety of administering intraoperative radiation with the Xoft System has been established in this cohort. Preliminary GLIOX Trial findings demonstrate the safety and feasibility of using the Xoft Axxent® Electronic Brachytherapy System to administer intracranial radiation during resection of recurrent glioblastomas. We will report new and expansive study results to include these early findings.
CTNI-52. A RANDOMIZED CONTROLLED TRIAL OF BERUBICIN, A DOXORUBICIN ANALOG THAT EFFECTIVELY CROSSES THE BLOOD-BRAIN BARRIER (BBB), AFTER FIRST-LINE THERAPY FOR GLIOBLASTOMA MULTIFORME (GBM): PRELIMINARY RESULTS
Authors: Silberman Sandra , Hsu Sigmund , Picker Don , Muzyczenko Zena , Priebe Waldemar 
Published: November 2022

Abstract
Berubicin is a doxorubicin (Dox) analog that crosses the BBB with significant central nervous system (CNS) uptake. Berubicin prolongs survival in orthotopic mouse intracranial models with greater infiltration of the tumor compared to normal tissue. A Phase 1 dose-escalation study showed myelosuppression as the dose-limiting toxicity, with 1 complete response (14+ years), 1 partial response durable for 12 weeks, and 9 patients with stable disease for a clinical benefit rate of 44%.A trial of Berubicin vs Lomustine in patients with recurrent GBM after first-line therapy in the US and EU is enrolling patients in a 2:1 randomization design of Berubicin:Lomustine. Patients will be stratified by MGMT methylation status. The primary endpoint is overall survival (OS) and secondary endpoints include progression-free survival and overall response rates. Advanced imaging technology is being utilized for consistency in the evaluation of MRI scans. An interim futility analysis to explore the relative efficacy of these drugs will be conducted after up to half of the patients enrolled have reached 6 months of therapy. Currently, 31 patients are enrolled with 21 in the Berubicin arm and 10 in the Lomustine arm. At present these patients show comparable demographics, with an unmethylated MGMT population of ~60% in both arms. Patients with all grades of adverse events were 57% and 60% on the Berubicin and Lomustine arms, respectively. Grade 3-4 events were 43% (Berubicin arm) and 30% (Lomustine arm). Less than 10% of patients discontinued the study due to adverse events.The available data to date shows that Berubicin and Lomustine arms are presently balanced with relatively comparable safety profiles. This study is continuing to evaluate the efficacy of this novel drug with the goal of providing therapeutic options for patients after first-line therapy. An updated patient population profile, safety, and initial efficacy will be presented.
CTNI-54. A PHASE 0/1 ‘TRIGGER’ TRIAL OF RIBOCICLIB PLUS EVEROLIMUS IN RECURRENT HIGH-GRADE GLIOMA
Authors: Sanai Nader , Tien An-Chi , Jiang Jun , Chang Yu-Wei , Montgomery Chelsea , DeSantis Anita , Fujita Yoko , Kim Seongho , Mehta Shwetal 
Published: November 2022

Abstract

BACKGROUND
The RB-CDK4/6 and mTOR signaling pathways are deregulated in high-grade glioma (HGG) and mTOR activation is a potential mechanism of resistance to CDK4/6 inhibition. This study evaluates the tumor pharmacokinetics (PK) and pharmacodynamics (PD) of combined CDK4/6 and mTOR inhibition in recurrent HGG patients.

METHODS
Eligible patients had recurrent HGG with (1) RB+, (2) CDKN2A/B deletion or CDK4/6 amplification, and (3) PTEN loss or PIK3CA mutations. Six patients received five days of ribociclib (400mg QD) plus everolimus (2.5mg QD) and underwent tumor resection at 2, 8 or 24 hours following the last dose. Six dose-escalation cohorts (n = 3 each) reached a dose-level of ribociclib (600mg QD) plus everolimus (70mg QW). Tumor tissue, CSF, and plasma were collected. Total and unbound drug concentrations were determined using validated LC-MS/MS methods. Tumor PD effects were compared to matched archival tissue. A PK ‘trigger’ (i.e., unbound concentration &gt; 5-fold biochemical IC50) and a PD ‘trigger’ ( &gt;30% decrease in both pRB and pS6) in Gd-nonenhancing tissue were set to qualify patients for expansion.

RESULTS
24 patients with WHO Grade III (n = 2) and Grade IV (n = 22) gliomas were enrolled. No dose-limiting toxicities were observed. Following presurgical drug, all patients demonstrated marked decrease in Gd-enhancement on preoperative MRI. In Gd-nonenhancing tumor regions, the median unbound concentration of ribociclib was 561 nM whereas no unbound everolimus concentrations were detected. Across all dose-levels, 57% (13/23) and 43% (10/23) of tumors demonstrated RB and S6 phosphorylation decrease, respectively.

CONCLUSION
In adult HGG, ribociclib achieves pharmacologically-relevant concentrations in Gd-nonenhancing tumor. Everolimus exhibits limited penetration into human glioma tissue. Our study supports further development of ribociclib, but not everolimus, for the treatment of glioma patients.
CTNI-57. RADIONUCLIDE THERAPY WITH 177LU-DOTATATE (LUTATHERA) IN ADULTS WITH ADVANCED INTRACRANIAL MENINGIOMA - INTERIM ANALYSIS RESULTS OF A SINGLE-ARM, OPEN-LABEL, MULTICENTER PHASE II STUDY
Authors: Kurz Sylvia , Zan Elcin , Cordova Christine , Barbaro Marissa , Troxel Andrea , Silverman Joshua , Snuderl Matija , Zagzag David , Golfinos John , Kondziolka David , Sulman Erik 
Published: November 2022

Abstract

BACKGROUND
While most meningiomas are considered benign tumors, a subset of these tumors are characterized by a more aggressive clinical course and require multimodal treatment. Beyond surgical and radiotherapeutic options, there are no effective medical treatments available. Somatostatin receptor 2 (SSTR2) is expressed by the majority of meningiomas. 177Lu-DOTATATE is a SSTR2-targeting radionuclide that has been successful in neuroendocrine tumors. Here we report the results of the interim analysis of an ongoing clinical trial (NCT03971461) that is evaluating the effect of 177Lu-DOTATATE in treating progressive intracranial meningiomas.

METHODS
In this Simon two-stage design phase II study, adults with advanced intracranial meningiomas received 177Lu-DOTATATE 7.4 GBq (200 mCi) every eight weeks for four doses. 68Ga-DOTATATE PET-MRI was performed before and at the end of treatment. The primary endpoint was progression-free survival at 6 months (PFS-6). Correlative studies evaluated the association of PFS-6, objective response rate, progression-free survival, overall survival with radiographic tumor measurements, 68Ga-DOTATATE uptake on PET-MRI, SSTR2 expression in tumor, and meningioma methylation subclass.

RESULTS
Fourteen patients (F = 11, M = 3) with progressive meningiomas (WHO I = 3, II = 10, III = 1) have been enrolled. Median age was 63.1 (range 49-78) years. All patients previously underwent tumor resection and at least one course of radiation. Treatment with 177Lu-DOTATATE was well tolerated, no treatment-limiting toxicities were observed. Six of 14 patients (42%) achieved PFS-6. Radiographically, all six patients had achieved Stable Disease. A functional alteration of tumoral SSTR2 expression by 68Ga-DOTATATE PET-MR imaging was observed in three patients.

CONCLUSIONS
Treatment with SSTR2-targeting 177Lu-DOTATATE is well tolerated. In this interim analysis, six of 14 patients achieved PFS-6. This exceeds the predefined threshold to continue to stage two of this study. This clinical trial is now open to patient enrollment at two study sites in the US.
CTNI-58. IMPROVING TRIAL ACCESS FOR PEOPLE WITH RARE CNS TUMORS: AN NCI-CONNECT PHASE I/II TRIAL OF PLX038 IN TUMORS WITH MYC/MYCN AMPLIFICATIONS INCORPORATING CORRELATIVE STUDIES AND PATIENT REPORTED OUTCOMES
Authors: Penas-Prado Marta , Wooley Joseph , Jung Jinkyu , Yuan Ying , Zhang Meili , Baranello Laura , Briceno Nicole , Levens David , Mendoza Tito , Pommier Yves , Thomas Craig , Vera Elizabeth , Santi Daniel , Armstrong Terri , Gilbert Mark 
Published: November 2022

Abstract

MYC genes encode transcription factors that regulate expression of genes involved in cell division. Supraphysiologic levels of MYC drive oncogenesis in many human cancers and induce the formation of topoisome complexes, essential to managing the torsional strain that would otherwise oppose transcription and replication. MYC/MYCN amplifications are seen in multiple primary CNS tumors including 30% of relapsed medulloblastomas (MB) and a subtype of ependymoma (EPN) where MYCN amplification defines the tumor. PLX038 is a PEGylated macromolecule containing the topoisomerase I inhibitor SN-38. PEGylations lead to longer half-life, tumor accumulation and decreased toxicity. We hypothesize that PLX038 will be efficacious in primary CNS tumors driven by MYC/MYCN amplifications by targeting the MYC-induced topoisome (Das, S.K. 2022 DOI10.1016/j.molcel.2021.11.016).

METHODS
Trial in development. Design/Objectives: Phase I (N = 12) – determine the maximum tolerated dose and recommended phase 2 dose of PLX038 in recurrent primary CNS tumors using TITE-BOIN design. Phase II - 3 independent cohorts, N = 30 for each group with interim analysis after 10 each: 2A - MYC-N amplified EPN post resection and radiotherapy (PFS); 2B - Recurrent MYCN amplified EPN or MYC/MYCN amplified MB (disease control rate, DCR); 2C - Other recurrent primary CNS tumors with MYC/MYCN amplifications (DCR). Additional measures: PROs from the Office of Patient-Centered Outcomes Research (OpCORe) web-based early phase trial endpoints; biomarkers of PLX038 distribution and response/resistance in peripheral blood, tumor tissue, hair follicles, and abdominal wall fat pad tissue.

CONCLUSIONS
NCI-CONNECT’s commitment to innovative designs can mitigate some of the barriers to access experimental therapy for people with rare CNS tumors. This basket trial will enroll participants with unifying molecular features and potential susceptibility to PLX038 despite different histological diagnoses. Furthermore, incorporation of comprehensive PROs will help identify clinical benefit and tolerability while correlative studies in tumor and other tissues will help identify biomarkers of response or resistance.
CTNI-67. DUAL INHIBITION OF POST-RADIOGENIC ANGIO-VASCULOGENESIS BY OLAPTESED PEGOL (NOX-A12) AND BEVACIZUMAB IN GLIOBLASTOMA – INTERIM DATA FROM THE FIRST EXPANSION ARM OF THE GERMAN PHASE 1/2 GLORIA TRIAL
Authors: Giordano Frank , Layer Julian , Leonardelli Sonia , Friker Lea , Schaub Christina , Turiello Roberta , Sperk Elena , Mildenberger Iris , Grau Franziska , Paech Daniel , Pietsch Torsten , Mueller Wolf , Grauer Oliver , Renovanz Mirjam , Tabatabai Ghazaleh , Kebir Sied , Glas Martin , Bisdas Sotirios , Hambsch Peter , Seidel Clemens , Hölzel Michael , Herrlinger Ulrich 
Published: November 2022

Abstract

BACKGROUND
We recently reported favorable safety, promising clinical efficacy and immunohistochemical indicators of response after radiotherapy (RT) plus escalating doses of the CXCL12-neutralizing RNA-Spiegelmer olaptesed pegol (NOX-A12) for glioblastoma in the German multicenter phase 1/2 GLORIA trial (NCT04121455). Here, we report outcomes after RT plus dual inhibition of vasculogenesis (NOX-A12) and angiogenesis (bevacizumab).

METHODS
After establishing safety in the monotherapy arm, we enrolled six patients with incompletely resected GBM, ECOG ≤ 2, age ≥ 18 and without MGMT promoter hypermethylation into a pre-planned expansion arm. Patients received standard RT (60 Gy in 30 fractions), continuous i.v. infusions of NOX-A12 (600 mg/week) and i.v. infusions of bevacizumab (10 mg/kg q2w). The primary endpoint was safety. Secondary endpoints included radiographic response, perfusion/diffusion imaging and neurologic performance.

RESULTS
Dual treatment was well-tolerated and safe. Of all G ≥ 2 AEs (n = 37), two G2 events (5.4%) were deemed related to NOX-A12. There were no dose-limiting toxicities and no treatment-related deaths. Longitudinal NANO assessment revealed stable neurologic functioning in all patients. Five out of six patients achieved partial responses (PRs) as per mRANO in week 9. All PRs remained durable at a median follow up of 5.6 months (range 3.6 to 9.3 months). No progression occurred. The mean best response was -65.9% (-13.3% to -99.9%) for target lesion sums and -92.1% (-76.2% to -100%) for non-target lesion (NTL) sums. In all three patients with NTL at least one lesion disappeared. The mean best change from baseline of the highly perfused-tumor fraction was -84.5% (-51.9% to -100%) and the mean best change of the apparent diffusion coefficient was 20.1% (-24.5% to 59.1%).

CONCLUSION
Interim data of the ongoing trial confirm the previously established safety profile of NOX-A12 and suggest improved efficacy of dual inhibition of post-radiogenic angio- and vasculogenesis by the addition of bevacizumab.
DNAR-08. THE ROLE OF SMARCAL1 AS A SYNTHETIC LETHAL VULNERABILITY IN ATRX-DEFICIENT GLIOMAS
Authors: Waitkus Matthew , Liu Heng , Brown Alexandrea , Strickland Laura , Khambati Taher , Fraley Casey , Diplas Bill , Keir Stephen , Ashley David 
Published: November 2022

Abstract
Mechanisms to maintain telomere length over successive cell divisions are a requirement for cancer cell immortalization. Although many cancers maintain telomere length through the activation of telomerase, ~10-15% of human cancers use telomerase-independent mechanisms of telomere maintenance, termed Alternative Lengthening of Telomeres (ALT). In gliomas, the ALT phenotype is associated with loss-of-function mutations in the ATRX gene in IDH-mutant astrocytomas, adult and pediatric glioblastomas (GBM), high-grade astrocytomas with piloid features, and pleomorphic xanthoastrocytomas. In adult GBM, we previously identified a relatively rare subset of ALT-positive ATRX wildtype tumors that harbored loss-of-function mutations in the SMARCAL1 gene, and we found that loss of SMARCAL1 activity plays a causative role in the onset of ALT in these tumors. SMARCAL1 is an annealing helicase that localizes to sites of DNA damage and replication stress and catalyzes the reversal of stalled replication forks. To better understand the relationship between ATRX mutations, SMARCAL1 activity, and the ALT phenotype, we investigated the localization and function of SMARCAL1 in ALT-positive glioma cells and xenografts with native ATRX deficiency. We found that SMARCAL1 localizes to ALT-associated PML bodies in astrocytoma cell lines with concurrent ATRX and IDH1 mutations (derived from grade 3 and 4 tumors). Our data show that inducible suppression of SMARCAL1 via doxycycline-induced RNAi leads to increased DNA double-strand breaks, increased abundance of extrachromosomal telomeric repeats (c-circles), and increased sensitivity to irinotecan, a topoisomerase I inhibitor. In an orthotopic mouse model, SMARCAL1 depletion exhibited a chemosensitizing effect in combination with irinotecan against a patient-derived xenograft (astrocytoma, IDH-mutant Grade 4). Based on these data, we hypothesize that SMARCAL1 activity is critical for resolving ALT-associated replication stress in ATRX-deficient malignant gliomas. We therefore propose that SMARCAL1 functions as a synthetic lethal vulnerability in ATRX-deficient ALT-positive gliomas and that SMARCAL1 inhibition is a viable therapeutic strategy in these tumors.
DNAR-13. SONIDEGIB AND GANT61 INDUCE DNA DAMAGE IN PEDIATRIC SONIC HEDGEHOG MEDULLOBLASTOMA
Authors: Price Laura , Lau Bonnie 
Published: November 2022

Abstract
Medulloblastoma is the most common malignant brain tumor in children, accounting for 20-25% of all pediatric brain tumors. The current standard of care includes both craniospinal and focal radiation therapy which leads to long term consequences in the pediatric population such as bone and tissue hypoplasia, decreased neurocognitive functioning, as well as an increased risk for secondary radiation induced cancers. Thus, there is a need for novel approaches to radiation therapy that can effectively target and kill tumor cells while minimizing radiation toxicity in healthy tissue in the pediatric patient population. The dysregulation and constitutive activation of the Sonic Hedgehog (SHH) signaling pathway accounts for ~30% of all medulloblastomas. In addition to playing a role in tumorigenesis, the SHH pathway is known to play a role in the radiation sensitivity and risk of tumor recurrence. We hypothesize that inhibiting the SHH pathway at Smoothened (Smo) or Gli1 will increase DNA damage, resulting in increased cell killing following radiation therapy. We found that treatment of medulloblastoma cells with the drug Sonidegib or GANT61 decreased the expression of the respective targets Smo and Gli1. Both drugs also significantly decreased expression of FANCD2, a DNA damage repair gene essential for homologous recombination. Pretreatment with Sonidegib or GANT61 resulted functionally with decreased tumor cell viability and self-renewal following radiation. These data suggest that Smo and Gli1 inhibition are promising targets for increasing the radiation sensitivity of pediatric SHH medulloblastoma.
DNAR-14. Y-BOX BINDING PROTEIN 1 REGULATES MEDULLOBLASTOMA TUMOR BIOLOGY AND THERAPEUTIC RESPONSE
Authors: McSwain Leon , Chen Victor , Huang Tiffany , Zhou Grace , Kenney Anna 
Published: November 2022

Abstract

BACKGROUND
Medulloblastoma (MB) is the most common pediatric brain tumor. MB can be dividing into 4 genetically distinct subgroups (Sonic Hedgehog (SHH), Wingless (WNT), Group 3, and Group 4). Most patients receive radiation and cisplatin backbone therapy. SHH and Group3 patients demonstrate poor prognosis, especially in cases of MYC amplification or p53 mutation. Given the continued reliance on DNA damage therapies, and our groups previous findings that YB1 regulates IGF2 transcription in SHH MB, we chose to investigate the role of YB1 in the DNA damage response and we performed RIPseq to understand mRNAs regulated by YB1 that may be targeted as novel therapeutics.

METHODS
Cell lines include primary MBCs derived from NeuroD2-SmoA1 SHH mice, ONS-76 human SHH, Daoy human SHH, D341 and D425 Human Group 3. YB1 overexpression or knockdown followed by radiation and assessment of yH2AX (a marker of DNA de-condensation following damage), Comet assay (a marker of physical damage), and proliferation time courses were used to assess effects of YB1 modulation on radiation response. RIPseq and YB1 knockdown were used to assess the effects of YB1 on PLXND1 levels. Scratch assay and western blotting of EMT markers were used to assess effects of PLXND1 silencing on migration.

RESULTS
(Radiation Studies) Overexpression of YB1 in primary MBCs followed by allograft into BL6 mice results in decreased overall survival. YB1 silencing followed by radiation results in faster resolution of yH2AX, faster resolution of damage, and lack of pRPA32 accumulation. YB1 silencing sensitizes cells to radiation resulting in substantial decreases in proliferation. (RNA Binding Protein Studies) YB1 binds and positively regulates PLXND1 translation. Silencing PLXND1 results in decreased migration and EMT mark expression.

CONCLUSIONS
YB1 drives a more error prone non-homologous End-Joining based mechanism of repair and binds and regulates PLXND1 post-transcriptionally. PLXND1 drives a migratory phenotype in SHH MB.