bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-26. SURGICAL WINDOW OF OPPORTUNITY TRIAL OF NAVTEMADLIN (KRT 232; AMG232) IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Lee Eudocia , Rudek Michelle , Rendo Veronica , Khuu Nicholas , Walbert Tobias , Holdhoff Matthias , Lieberman Frank , Desai Arati , Strowd Roy , Lapinskas Emily , Pelton Kristine , Pisano William , Desideri Serena , Danda Neeraja , Fisher Joy , Ye Xiaobu , Nabors L Burt , Grossman Stuart , Beroukhim Rameen , Alexander Brian , Ligon Keith , Wen Patrick Y 
Published: November 2022

Abstract

BACKGROUND
KRT232 is an orally bioavailable, selective small molecule inhibitor of MDM2 that blocks the protein-protein interaction between MDM2 and p53. We performed a surgical window of opportunity trial of KRT232 in patients with recurrent GBM.

METHODS
The primary endpoint was to determine the tumor tissue concentration of KRT232. Prior to surgery, patients received KRT232 at either 120mg (n = 10, minimal dose that is consistently associated with alterations in serum MIC-1) or 240mg (n = 10; recommended phase 2 dose as monotherapy) for two days prior to surgical resection. Surgery was performed 3-6 hours following the last administration of KRT232. Tissue was analyzed for KRT232 concentration by LC/MS and for correlative studies. Participants with TP53 wild-type tumors were eligible to continue KRT232 following recovery from surgery at the RP2D of 240mg QD x 7 days q3weeks.

RESULTS
Twenty-one patients were enrolled from July 2018 to April 2020. One patient was deemed ineligible after surgery due to non-GBM tumor. Study met the prespecified criteria of target intra-tumor drug concentration of ≥ 25nM in contrast enhancing tissue in more than 50% of the patients in the 120mg cohort (67.1 ± 42.7nM in 8/10 patients) and 240mg (328.7 ± 468.1nM in 10/10 patients) cohort. Serum MIC-1 fold-changes from baseline (FCB) approximately 24 hours after a single dose of KRT232 were higher in the 240mg cohort (9.1 ± 4.1-FCB) than the 120mg cohort (3.6 ± 2.0-FCB). CDKN1A (p21), a downstream marker of p53, was significantly upregulated in analyzed participants whose GBM was TP53 wildtype, but not in TP53 mutant GBM or control samples (GBM treated with standard of care).

CONCLUSION
KRT232 at both 120mg and 240mg achieves adequate tumor tissue penetration and affects downstream pathways in TP53 wildtype GBM. The study has moved to Alliance to complete a phase 1 study of radiation + KRT232 in patients with newly diagnosed MGMT unmethylated GBM.
CTNI-27. MULTI-CENTER, PHASE 2 STUDY EVALUATING THE PHARMACOKINETICS, SAFETY AND PRELIMINARY EFFICACY OF PAXALISIB IN NEWLY DIAGNOSED ADULT PATIENTS WITH UNMETHYLATED GLIOBLASTOMA (GBM)
Authors: Wen Patrick Y , de Groot John , Battiste James , Goldlust Samuel , Damek Denise , Ellingson Benjamin , Garner James , Friend John , Simpson Jeremy , Olivero Alan , Cloughesy Timothy 
Published: November 2022

Abstract
NCT03522298 was an open-label, multi-center, 2-stage trial designed to establish the maximum tolerated dose (MTD) for once-daily (QD) paxalisib dosing (Stage 1), then evaluate pharmacokinetics(PK) and safety and explore efficacy (Stage 2). Eligible patients had undergone surgical resection and chemoradiotherapy (EORTC 26981–22981/NCIC CE3), had a life expectancy of ³ 12 weeks and were progression free before starting adjuvant paxalisib. Stage 1 used a standard 3 + 3 dose-escalation design to determine the MTD. Stage 2 was a two-arm, open-label, expansion cohort with patients randomized 1:1 to receive paxalisib at the MTD under fed or fasted conditions. In both stages, treatment comprised daily paxalisib administered in continuous 28-day cycles, until disease progression or unacceptable toxicity. Patients (n = 30; 70.0% males, mean age 58.5 years, mean 3.75 months since diagnosis) received paxalisib for a mean duration of 99 (9-833) days. In Stage 1 (n = 9), an MTD of 60mg was established on the dose-limiting toxicities of hyperglycemia (n = 1) and stomatitis (n = 1) at 75mg. Paxalisib was well-tolerated with no unexpected safety signals. Adverse events (37%) or progressive disease (33%) were the primary reasons for treatment discontinuation. At the MTD, the PK profile was linear and dose-proportional with no differences in Tmax and elimination half-life under fed/fasted conditions. Ten patients underwent FDG-PET imaging, 8 (80%) had a decrease in FDG uptake on Day 3 and/or Day 7 in Cycle 1; 4 (40%) had a metabolic partial response. From date of diagnosis, progression free survival (mRANO, investigator review) was 8.6 months and overall survival was 15.7 months. Primary study outcomes (1) MTD of 60mg was established for QD dosing and (2) PK and safety were consistent with prior clinical experience. Preliminary efficacy signals were encouraging and further investigation of paxalisib 60mg QD in newly diagnosed and recurrent GBM is ongoing in a pivotal trial (GBM AGILE, NCT03970447).
CTNI-31. COG ACNS1721: PHASE 2 STUDY OF VELIPARIB AND LOCAL IRRADIATION, FOLLOWED BY MAINTENANCE VELIPARIB AND TEMOZOLOMIDE, IN PATIENTS WITH NEWLY DIAGNOSED HIGH-GRADE GLIOMA WITHOUT H3 K27M OR BRAF MUTATIONS
Authors: Karajannis Matthias , Thomas Arzu Onar , Baxter Patricia , Butingan Nina , Fuller Christine , Gajjar Amar , Haque Sofia , Jabado Nada , Lin Tong , Lucas John , MacDonald Shannon , Matsushima Celeste , Patel Namrata , Pierson Christopher , Springer Linda , Stark Eileen , Souweidane Mark , Walsh Michael , Zaky Wafik , Fouladi Maryam , Cohen Kenneth 
Published: November 2022

Abstract

BACKGROUND
The outcome for pediatric patients with high-grade glioma (HGG) remains poor. Veliparib, a potent oral PARP1/2 inhibitor, enhances the activity of radiotherapy and DNA-damaging chemotherapy. Preclinical data indicates that veliparib crosses the blood-brain-barrier and enhances the efficacy of radiotherapy and temozolomide in IDH mutant and wild-type HGG models. ACNS1721 was a single-arm, non-randomized phase 2 clinical trial designed to determine whether treatment with veliparib and radiotherapy, followed by the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib and temozolomide, improves progression-free survival (PFS) in pediatric patients with newly diagnosed HGG without H3 K27M or BRAF mutations compared to patient level data from historical cohorts with closely matching clinical and molecular features.

METHODS
Following surgical resection, newly diagnosed children with non-metastatic HGG were screened by rapid central pathology review and molecular testing. Eligible patients without somatic H3 K27M or BRAF mutations were enrolled on Stratum 1 (IDH wild-type) or Stratum 2 (IDH mutant). Protocol radiochemotherapy consisted of involved field radiotherapy with concurrent veliparib at 65 mg/m2 twice daily. Adjuvant chemotherapy consisted of up to 10 cycles of veliparib 25 mg/m2 twice daily and temozolomide 135 mg/m2 once daily for 5 days every 4 weeks.

RESULTS
Both strata were closed to accrual for futility after planned interim analyses. Among the 23 eligible patients who enrolled on Stratum 1 and received protocol therapy, the 1-year progression-free survival (PFS) was 0.29 (SE = 0.09) and 1-year overall survival (OS) was 0.67 (SE = 0.10). Among the 14 eligible patients who enrolled on Stratum 2 and received protocol therapy, the 1-year PFS was 0.57 (SE = 0.15) and 1-year OS was 0.90 (SE = 0.09).

CONCLUSION
Rapid central pathology review and molecular testing was feasible. The protocol therapy was well tolerated but failed to improve outcome compared to clinically and molecularly matched historical control cohorts.
CTNI-32. PHASE 2 STUDY OF VAL-083 AND RADIOTHERAPY IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM
Authors: Chen ZhongPing , Guo Chengcheng , Chen JianGen 
Published: November 2022

Abstract
VAL-083 is a novel bi-functional DNA targeting agent that induces inter-strand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and cell death. In vitro and in vivo studies have demonstrated VAL-083 circumvents MGMT-mediated chemoresistance and differentiates it from other therapies used in the treatment of GBM, including temozolomide (TMZ). VAL-083 also acts as a radiosensitizer against GBM cancer stem cells in vitro. A Phase 2 study was conducted to evaluate the safety and tolerability of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT unmethylated GBM. Stage 1 was a dose-escalation phase to confirm the dose of VAL-083 in this setting. Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days in combination with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 with RT. A total of 29 patients were enrolled in the study and completed treatment, with 25 patients receiving 30 mg/m2/day VAL-083. The median number of cycles completed by all patients was 9 (range 2-13). Consistent with our prior experience, myelosuppression was the most common adverse event. Pharmacokinetics (Cmax and AUC) of VAL-083 were broadly linear with respect to dose, and drug half-life was 0.8 hrs. In a sub-group of patients, levels of VAL-083 in CSF were found to be at least as high as those in plasma. The median progression free survival (PFS) for all patients enrolled was 9.3 (95%CI: 6.4-12.0) months. Eighteen (18/29; 62.1%) patients have died, and median overall survival for all patients enrolled was 19.6 (95%CI: 14.0-22.4) months. These results support the potential benefit of VAL-083 as a treatment alternative against GBM tumors with MGMT-mediated resistance to TMZ. Clinicaltrials.gov: NCT03050736.
CTNI-35. PHASE 0/1 TRIAL OF MYCOPHENOLATE MOFETIL COMBINED WITH CHEMORADIATION TO OVERCOME TREATMENT RESISTANCE IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA BY TARGETING PURINE METABOLISM
Authors: Umemura Yoshie , Al-Holou Wajd , Marini Bernard , Leung Denise , Kim Michelle , Ferris Sean , Junck Larry , Sagher Oren , Heth Jason , Sun Yilun , Schipper Matthew , Lyssiotis Costas , Lawrence Theodore , Wahl Daniel 
Published: November 2022

Abstract

BACKGROUND
Purine metabolism promotes glioblastoma growth, stemness, invasiveness, and treatment resistance. The purine synthesis inhibitor, mycophenolate mofetil (MMF), improves radiation and temozolomide efficacy in preclinical glioblastoma models. This phase 0/1 trial (NCT04477200) aims to determine the maximum-tolerated dose of MMF combined with chemoradiation in glioblastoma. It also aims to quantify the levels of the active metabolite of MMF and the extent of purine synthesis inhibition in enhancing and non-enhancing tumor tissue.

METHODS
Key eligibility criteria are age ≥ 18 and KPS ≥ 60%. TITE-CRM dose-escalation is used for MMF dosing starting at 1000mg PO BID (range 500-2000mg BID). Thirty recurrent glioblastoma patients receive MMF one-week prior to and concurrently with re-irradiation (40.5 Gy in 15 fractions), with 28 days of dose-limiting toxicity (DLT) period. Thirty newly diagnosed glioblastoma patients receive MMF one-week prior to and concurrently with standard radiation with concurrent temozolomide and followed for 28 days for DLT1-period, then MMF is given days 0-5 of each adjuvant cyclic temozolomide using a separate dose-escalation with the first two cycles as the DLT2-period. In phase 0, eight recurrent glioblastoma patients receive MMF 500-2000mg PO BID one-week pre-operatively and tissues are analyzed using mass spectrometry.

RESULTS
Eighteen phase 1 subjects (11 recurrent, 7 new) have received study treatment with no DLT to date up to MMF 2000mg BID. Main toxicities are mild nausea, fatigue, and elevated liver enzymes. No notable study-related hematotoxicity nor opportunistic infection have been observed. The active metabolite of MMF accumulated to active concentrations in enhancing and non-enhancing tumor tissue and appeared to inhibit purine synthesis.

CONCLUSION
MMF combined with chemoradiation has been reasonably well tolerated in glioblastoma patients with preliminary evidence of intracranial target engagement of its active metabolite. This study will yield a recommended phase 2 dose and preliminary efficacy estimate for future randomized phase 2/3 trial.
CTNI-36. INITIATION OF A PHASE 1 DOSE-ESCALATING STUDY OF WEEKLY DIRECT-TO-BRAIN ADMINISTRATION OF SOLUBILISED FORMULATION OF PANOBINOSTAT (MTX110) IN PATIENTS WITH RECURRENT GLIOBLASTOMA (MAGIC-G1 STUDY)
Authors: Desjardins Annick , Conlon Kelly , Gunning Hannah , Davies Rhian , Komisarow Jordan , Cavaliere Robert , Zamoryakhin Dmitry 
Published: November 2022

Abstract

INTRODUCTION
Glioblastoma (GBM) is the most aggressive primary brain tumour in adults, leading to universal recurrence despite aggressive surgical and chemotherapeutic treatment. Post-recurrence, median overall survival is 6 to 10 months and treatment options are very limited. One of the biggest challenges in treating GBM is achieving high local drug concentration; systemic administration of cytotoxic agents has failed in the past due to this limitation. Convection enhanced delivery (CED) is a ‘direct-to-brain’ drug delivery method that previously demonstrated its usefulness in overcoming this challenge. MTX110 (Midatech Pharma Ltd) is a water-soluble form of panobinostat, that demonstrated cytotoxic activity in 4 GBM cell lines (U87MG, U251MG, U118MG and T98G) with an average IC50 value around 40nM which also translated into pre clinical in vivo efficacy, in combination with radiotherapy1. Delivery of MTX110 via an implanted pump and CED catheter system in patients with GBM appears to be an attractive treatment option, that allows for therapeutic doses of the drug to be delivered weekly directly to the tumour, thus avoiding systemic administration and therefore toxicity. This has previously been demonstrated in investigator-initiated studies of paediatric patients with diffuse intrinsic pontine glioma.

METHOD
MAGIC-G1 study is a Phase 1 two-cohort dose-escalating study that will assess safety and feasibility of intermittent intratumoral administration of MTX110 by CED to rGBM patients; either as a single agent (Cohort 1) or in combination with lomustine (Cohort 2). Eligible patients will have a catheter system and an abdominal refillable pump implanted in an aseptic manner, with the tip of the catheter positioned stereotactically at the centre of the tumour. 48-hour infusions will be administered weekly until disease progression and doses of 30, 60 and 90 mM will be investigated. Cohort 1 recruitment will be completed before Cohort 2 starts dosing. Study results are expected in 2023.
CTNI-40. PHASE I TRIAL OF SULFASALAZINE COMBINED WITH STEREOTACTIC RADIOSURGERY FOR RECURRENT GLIOBLASTOMA: STUDY PROTOCOL FOR NCT04205357
Authors: Skeie Bente Sandvei , Bragstad Sidsel , Sarowar Shahin , Behbahani Maziar , Filippi Christopher , Knisely Jonathan , Schulder Michael , Goplen Dorota , Eide Geir Egil , Heggdal Jan Ingemann , Gruner Renate , Enger Per Øyvind 
Published: November 2022

Abstract
Glioblastoma (GBM) is one of the most aggressive, radioresistant types of cancer with a dismal prognosis. Sulfasalazine (SAS) has shown tumor selective radiosensitizing properties in preclinical studies. The antioxidant glutathione (GSH) produced at high levels in glioma cells normally protects against radiation injury by scavenging reactive oxygen species produced during radiation therapy (RT). SAS blocks cysteine uptake through the xCT-channel, a rate-limiting step for GSH production. We have previously shown slowing of tumor growth and prolonged survival when SAS was combined with stereotactic radiosurgery (SRS) in vivo compared to either treatment alone. Our hypothesis is that SAS potentiates the efficacy of SRS for recurrent GBM with a low risk of adverse events (AE). The primary end-point is to establish the recommended dose for efficacy testing in phase II/III trials. This phase 1 dose-escalation trial utilizes a standard 3 + 3 design with 3-6 patients per cohort. Patients will be treated with oral SAS (1.5, 3.0, 4.5 or 6.0 g/day) 3 days prior to single session SRS. The SAS-dose will be escalated depending on the absence/presence of toxicity in the previous cohort of treated patients. If more than 1 of 3-6 patients ( ≥ 33 %) is experiencing grade 3 or higher toxicity levels, the study will be terminated. The dose below will be the recommended dose. Toxicity is graded using the Common Toxicity Criteria for Adverse Events (CTCAE) v5.0 recorded the first 30 days. Secondary end-points are assessments of 1) intratumoral GSH production (GSH-spectroscopy), 2) late AE utilizing 11C-MET-MRI-PET 3) changes in KPS/quality of life (FACT-Br), 4) need for steroidal treatment, 5) progression free and overall survival. Novel treatment modalities are urgently needed. This trial will establish the recommended dose for SAS repurposed as a radiosensitizer for a future phase 2/3 trial and may ultimately lead to improvement of current GBM treatment.
CTNI-43. COMBINATION OF TROFOSFAMIDE PLUS ETOPOSIDE IN RECURRENT ADULT-TYPE DIFFUSE GLIOMAS
Authors: Schmidt Teresa , Agkatsev Sarina , Feldheim Jonas , Oster Christoph , Blau Tobias , Sure Ulrich , Keyvani Kathy , Kleinschnitz Christoph , Stuschke Martin , Hermann Ken , Deuschl Cornelius , Scheffler Björn , Kebir Sied , Glas Martin , Lazaridis Lazaros 
Published: November 2022

Abstract
Disease relapse almost inevitably occurs in patients with adult-type diffuse glioma. Standard of care treatment options at tumor relapse are still not well defined. Few studies indicate that the combination of trofosfamide plus etoposide (T/E) may be feasible in pediatric glioblastoma patients. We collected clinicopathological data from adult patients with adult-type diffuse glioma treated with the combination of Trofosfamide (100mg/m2/day) and Etoposide (25mg/m2/day) for a minimum of four weeks at the Division of Clinical Neurooncology at the University Hospital Essen. T/E was administered orally in a “one week on, one week off” scheme. A cohort of patients receiving empiric treatment at the investigators’ discretion balanced for tumor entity and canonical prognostic factors served as control. We collected toxicity data as it pertained to CTCAE (Common Terminology Criteria for Adverse Events, version 5.0) and survival data to explore putative efficacy.A total of 33 patients were eligible for this analysis. In the IDH wild-type glioblastoma (n = 18) subgroup, median progression-free survival (3.8 months versus 2.9 months, HR: 2.09, 95% CI: 1.010-4.312, p = 0.0227; PFS-6: 39% versus 6%) and median overall survival (10.4 months versus 5.7 months, HR: 3.05, 95% CI: 1.393-6.655, p = 0.0008) were significantly prolonged as compared to the control cohort. In a multivariable Cox regression analysis, treatment with T/E emerged as statistically significant prognostic marker regarding progression-free survival and overall survival. We observed high-grade adverse events (CTCAE grade III or higher) in 21 (64%) of all recurrent glioma patients with hematotoxicity comprising most adverse events (n = 18, 86%; Lymphopenia: n=13, 62%). This study provides first indication that the combination of T/E is safe in patients with adult-type diffuse gliomas and may be associated with prolonged survival in adult patients with recurrent IDH wildtype glioblastoma. Our data provide a reasonable rationale for follow-up of a larger cohort in a prospective controlled trial.
CTNI-45. CLINICORADIOLOGICAL AND HISTOPATHOLOGICAL CHARACTERISTICS AND TREATMENT OUTCOMES OF CEREBRAL ASTROBLASTOMA IN CHILDREN: A SINGLE-INSTITUTION EXPERIENCE
Authors: Choi Jung Won , Jeon Chiman 
Published: November 2022

Abstract

OBJECTIVE
Astroblastoma (AB) is a rare glial tumor. The optimal treatment and prognosis of this tumor remain unclear. The authors retrospectively analyzed the clinical characteristics, neuroimaging findings, histopathological results, and treatment outcomes of 7 patients with AB.

METHODS
The study comprised 7 patients with pathologically proven AB who were surgically treated at Samsung Medical Center from November 1994 to January 2019. Clinicoradiological, histopathological, and surgical records were reviewed.

RESULTS
The patients included 5 girls (71.4%) and 2 boys (28.6%), with a median age of 13 years. All patients showed contrast enhancement on preoperative MRI: 5 ABs (71.4%) showed a concomitant solid and cystic appearance, and 2 (28.6%) demonstrated a solid appearance. ABs in 6 patients (85.7%) showed a well-circumscribed, characteristic "bubbly" appearance on T2-weighted MRI. Gross-total resection (GTR) was achieved in all cases (100%). Six patients (85.7%) were diagnosed with high-grade AB and 1 (14.3%) with low-grade AB. Six (85.7%) of the 7 patients received adjuvant treatment after resection, including 5 (83.3%) with AB who received chemotherapy and radiotherapy and 1 (16.7%) who received proton therapy alone. The median clinical follow-up duration was 96 months (range 48-189 months). Two patients experienced recurrence, and all patients in this series were alive at the last follow-up.

CONCLUSIONS
In this study, the clinicoradiological and histopathological features of AB were described. Based on the authors' limited experience with 7 cases, resection with the goal of GTR is currently the mainstream treatment for AB, and adjuvant radiation treatment should be considered after surgery.
CTNI-49. EARLY SIGNAL OF ACTIVITY FROM A PHASE 2 STUDY OF ST101, A FIRST-IN-CLASS PEPTIDE ANTAGONIST OF CCAAT/ENHANCER-BINDING PROTEIN Β (C/EBPΒ), IN RECURRENT GLIOBLASTOMA (GBM)
Authors: Iwamoto Fabio , Gondi Vinai , Butowski Nicholas , Falchook Gerald , Williams Anja , Peters Katherine B , Evans Jeff , Lakhani Nehal , McKean Meredith , Symeonides Stefan , Ellingson Benjamin , Rotolo Jim , Capiaux Gina , Wiegert Erol , Michel Rob , Kaesshaefer Steve , Bexon Alice 
Published: November 2022

Abstract

BACKGROUND
C/EBPβ is a transcription factor that is active during embryofetal development but held in an inactive state in most mature cells (Zahnow 2009). C/EBPβ activates a proliferation/survival gene signature in multiple cancers, where it inversely correlates with disease prognosis and survival. ST101 is a cell-penetrating peptide antagonist of C/EBPβ. ST101 exposure leads to selective tumor cell death in multiple human cancer cell lines, including GBM, without impacting normal cell viability. In vivo, ST101 displays rapid uptake into multiple organs, the ability to cross the blood-brain barrier, and a long plasma half-life due to its resistance to degradation. It has potent anti-tumor activity in multiple GBM models, as a single agent or in combination, which supported moving into clinical development. TRIAL DESIGN: This phase 2 study is enrolling adult patients with GBM that has recurred or progressed after one standard treatment regimen (surgery, radiotherapy +/-temozolomide). Patients require measurable disease at baseline and at least 3 months from prior radiotherapy. Subjects receive the recommended phase 2 dose of ST101 (500mg IV weekly). Recruitment in the phase 2 portion of this trial began in January, 2022.

RESULTS
As of June 1, 2022, 14 GBM patients were enrolled. One patient has a confirmed mRANO partial response (PR) after 18 weeks of therapy, seven patients have not reached the first on-study assessment and six patients progressed. The median duration of therapy was 5 weeks. ST101 has a favorable safety profile with minor infusion related reactions being the most common adverse event. Based on the confirmed PR, the GBM cohort will be expanded.

CONCLUSION
This first-in-class C/EBPβ inhibitor, ST101, showed an early signal of activity in recurrent GBM. More extensive follow-up and clinical experience will be presented as this trial expands and matures.