bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-28. FINAL RESULTS OF A PILOT STUDY TO EVALUATE INFUSION RATE ESCALATION TO MAXIMIZE VOLUME OF DISTRIBUTION DURING CONVECTION ENHANCED DELIVERY TO CONTRAST-ENHANCING GLIOBLASTOMA
Authors: Liu James , Tran Nam , Piteo Cecily , Matzza Sebastian , Forsyth Peter , Vogelbaum Michael A 
Published: November 2023

Abstract

BACKGROUND
Volume of distribution (Vd) during convection enhanced delivery is impacted by the characteristics of the tissue being treated. For Glioblastoma (GBM), Vd is substantially higher in non-contrast enhancing tumor than in contrast enhancing tumor due to higher infusate efflux in enhancing tumor. We hypothesized that increasing the infusion rate could overcome the infusate efflux rate in enhancing tumor to improve the Vd to volume of infusion (Vi) ratio and provide better tumor coverage.

METHODS
A single center, IRB-approved pilot study was conducted under an IND (held by MAV) to perform rate escalated delivery of Topotecan with Gadolinium-DTPA to contrast-enhancing recurrent GBM (rGBM). A single Cleveland Multiport Catheter was surgically placed into enhancing tumor and then a 4-hour infusion was performed with real-time MRI visualization. Intra- and inter-patient rate escalation was performed.

RESULTS
3 patients with rGBM were enrolled and treated. The initial infusion rate for patient 1 was 5 microliters/minute per microcatheter (4 total) and the final infusion rate for the third patient was 20 microliters/minute per microcatheter. We observed partial backflow at this rate and so did not escalate higher. There was coverage of both enhancing and non-enhancing tumor in all cases, and the Vd/Vi ratio ranged from 0.7 to 1.3. Patients tolerated the treatments well; there were no CTCAE Grade 3 or higher treatment related adverse events.

CONCLUSIONS
The higher efflux rate associate with contrast-enhancing tumor tissue can be overcome with sufficient infusion rate escalation.
CTNI-29. A PHASE 2 STUDY TO EVALUATE EFFICACY AND SAFETY OF ACT001 AND TEMOZOLOMIDE COMBINATION TREATMENT IN PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME
Authors: Li Wenbin , Li Qun , Wang Liang , Cai Dongpo , Yang Xunjun 
Published: November 2023

Abstract

BACKGROUND
Han Chinese patients with rGBM were randomly assigned to one of three cohorts in this phase 2 open label study: Arm A (ACT001, 400mg, BID), B (ACT001 and temozolomide combination) and C (TMZ or CCNU). Study endpoints include 1-year OS rate, PFS (by iRANO) and AE incidence.

RESULTS
7, 6 and 6 patients were enrolled to Arms A, B and C respectively including one patient in Arm C with a mutant IDH1 (R132H). The median age was 52 years (range: 34-68) and male to female ratio 11/8. In addition to 7 SAEs, 189 TEAEs were reported in this interim analysis including 49 and 70 chemo-related AEs in Arm B and Arm C. Post enrollment MRI scans were performed in 6,6 and 4 patients in Arms A, B and C respectively. Despite the lack of objective response and difference in 1-year OS, a prolonged PFS lasting at least 12 months was noted in 3 patients including the patient with mutant IDH1 in Arm C (23 months and ongoing) and two patients in Cohort B (19 and 22 months, both ongoing) who were sensitive to TMZ in first line treatment as shown by at least 12-month interval between TMZ initiation and first relapse. Among 18 patients with wild type IDH, the prolonged stable disease was restricted to combination Arm whereas either the four patients with positive MGMT methylation or two patients with a similar history of sensitivity to first line TMZ treatment didn’t have such prolonged stable disease after being treated with TMZ or ACT001 alone during this study.

CONCLUSIONS
ACT001 restored sensitization of rGBM patients to TMZ treatment in sub-group of patients likely due to reduced DNA repair capacity by ACT001 treatment. Further study is warranted to evaluate the effect of ACT001 and TMZ combination in phase 2b study.
CTNI-32. IMPLEMENTING GENOMIC PROFILING AS STANDARD-OF-CARE FOR GLIOBLASTOMA PATIENTS
Authors: Fougner Vincent , Urup Thomas , Hasselbalch Benedikte , Poulsen Hans , Rohrberg Kristoffer , Spanggard Iben , Højgaard Martin , Belcaid Laila , Yde Christina , Lassen Ulrik , Noeroexe Dorte 
Published: November 2023

Abstract

BACKGROUND
The introduction of targeted therapies (TT) has provided few new options for glioblastoma patients (pts). Implementing genomic profiling as standard-of-care may aid in finding new treatments for glioblastoma pts. Here, we report the impact of genomic profiling in pts with WHO grade 4 CNS tumors at the Department of Oncology, Rigshospitalet, Denmark.

METHODS
Eligible pts were ≥18 years of age, with newly diagnosed glioblastoma; astrocytoma, IDH mutated grade IV or diffuse midline glioma between January 2016 and December 2022. Whole exome sequencing (WES), whole genome sequencing (WGS) or panel sequencing with Trusight Oncology (TSO500) along with SNP-array analyses and RNAseq was performed on DNA/RNA extracted from tumor tissue. Tumor tissue from patients enrolled before 2021 were analyzed by WES, and from January 2021 and forth, WGS was used for frozen tissue and TSO500 for paraffin-embedded tissue. Each genomic profile was presented at a weekly national molecular tumor board meeting for multidisciplinary evaluation, treatment recommendations and matching with clinical trials.

RESULTS
387 pts had tissue samples available for analysis. Tissue from 202 patients (52%) were analyzed using WES, 174 (45%) using WGS, and 11 (3%) using TSO500. As of May 2023, of the 343 sequenced pts that have progressed after standard therapy, 14 patients (4%) have been treated with molecularly matched TTs. The actionable targets were TMB-high ( &gt;10mut/MB) (n = 4), FGFR-mutations/-fusions (n = 4), BRAFv600E (n = 2), NTRK-fusions (n = 2), PDGFRA-fusion (n = 1) and MET-mutation (n = 1). Additionally, germline mutations were reported in 8 patients (2%).

CONCLUSION
Genomic profiling revealed actionable targets and new therapeutic options for glioblastoma pts. A full and updated overview of patient characteristics, actionable targets and survival data will be presented at the meeting.
CTNI-35. A RANDOMIZED, CONTROLLED TRIAL OF BERUBICIN VS. LOMUSTINE AFTER FIRST-LINE THERAPY FOR GLIOBLASTOMA MULTIFORME (GBM): INTERIM RESULTS OF A PRE-PLANNED ANALYSIS OF OVERALL SURVIVAL (OS)
Authors: Silberman Sandra , Muzyczenko Zena , Hsu Sigmund 
Published: November 2023

Abstract
Berubicin is an analog of doxorubicin (Dox) that appears to cross the BBB with significant central nervous system (CNS) uptake. RESULTS: of a Phase 1 dose-escalation study with 25 patients evaluable for efficacy showed 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%. Our current, potentially pivotal trial for patients with recurrent GBM after first-line therapy is enrolling in the US and Europe. It is unique in that all patients must be Grade 4 IDH WT, classifying these tumors as a poorer prognostic population than Grade 4 IDH mutated. Patients are randomized in a 2:1 design of Berubicin:Lomustine and stratified by MGMT methylation status. The primary endpoint is OS. Data has been presented showing that Berubicin and Lomustine arms are balanced with respect to MGMT status and demographics, with relatively comparable safety profiles (SNO Annual Meeting 2022 Abstract #383142). A pre-planned non-binding futlity analysis of the primary endpoint, OS, is being evaluated when the trial reaches ~30% of expected events (44 events). The interim analysis will be performed by an independent statistician under the supervision of the Data Safety Monitoring Board (DSMB). The futility analysis will be based on the conditional power that the trial will be positive (e.g., statistically significant difference between treatment groups’ OS). If the conditional power is &lt;10% then the DSMB may recommend to end the study; otherwise the study will continue as it is currently planned. The review will also include safety and secondary efficacy endpoint summaries. RESULTS: of this interim analysis will be available for the SNO annual meeting and an evaluation of its outcome will be performed, with conclusions and recommendations for the further development of Berubicin as a therapeutic option for patients with recurrent GBM.
CTNI-36. SACITUZUMAB GOVITECAN FOR RECURRENT GLIOBLASTOMA
Authors: Kelly William , Balinda Henriette , Ghamasaee Pegah , Gilbert Andrea , Michalek Joel , Surapaneni Prathibha , Floyd John , Brenner Andrew 
Published: November 2023

Abstract
Glioblastoma (GBM) is an aggressive and highly malignant brain tumor characterized by its infiltrative growth, rapid progression, and poor prognosis. Sacituzumab govitecan (SG), an antibody-drug conjugate, has demonstrated antitumor activity and acceptable tolerability in patients with advanced epithelial cancers. It consists of a humanized anti-Trop-2 monoclonal antibody linked to a potent topoisomerase I inhibitor, SN-38. We conducted a prospective, single center, window of opportunity trial (NCT03995706) to examine the intra-tumoral concentrations of SN-38 in patients undergoing craniotomy for recurrent GBM (rGBM; n = 12). We enrolled patients aged ≥18 years diagnosed with rGBM to receive a single intravenous dose of SG at 10 mg/kg one day before surgical resection. Tumor and corresponding serum were collected during surgery to measure their levels of SN-38. Following recovery, patients resumed SG treatment at 10 mg/kg on days 1 and 8 of 21-day cycles and were accessed for responses by MRI every third cycle using response assessment in neuro-oncology (RANO) criteria. Trop-2 and carbonic anhydrase IX (CAIX) expression was investigated by IHC. An average of 2850.6 ng/ml in serum and 128.7 ng/g in tissue of SN-38 was quantified in our patient samples. Trop-2 expression was observed in 50% of patient tumors and 38% of the samples showed high expression of hypoxia marker CAIX. A strong positive correlation between the tissue/serum SN-38 and Trop-2 (r = 0.86, p = 0.01) was observed. Median overall survival of 17.5 months (0.9 - 28.5 months) and progression free survival of 2 months (0.5 - 12 months) were observed. A multicenter, phase II clinical trial has been initiated to further investigate the efficacy of SG in patients with breast brain metastasis. Updated data on response rates and accrual to the multicenter trial for rGBM will be presented
CTNI-38. RACTAC TRIAL: PHASE II MULTICENTRIC ITALIAN TRIAL ON REPOSITIONING OF THE ANTIPSYCHOTIC DRUG CHLORPROMAZINE AND ITS COMBINATION WITH TEMOZOLOMIDE IN MGMT UNMETHYLATED GLIOBLASTOMA PATIENTS
Authors: Pace Andrea , Lombardi Giuseppe , Villani Veronica , Benincasa Dario , Abruzzese Claudia , Cestonaro Ilaria , Corrà Martina , Cerretti Giulia , Caccese Mario , Silvani Antonio , Gaviani Paola , Giannarelli Diana , Paggi Marco 
Published: November 2023

Abstract
The poor prognosis of patients affected by glioblastoma (GBM) prompts the search for more effective therapies, particularly for GBMs with unmethylated MGMT. Drug repurposing, can represent a safe and inexpensive way to bring novel pharmacological approaches from bench to bedside. Chlorpromazine, a medication in use for psychiatric disorders, shows in vitro features that make it eligible for repositioning in GBM therapy. In our experimentation on six GBM cell lines, chlorpromazine inhibited cell viability, induced polyploidy, reduced cloning efficiency as well as neurosphere formation. Moreover, chlorpromazine synergized with temozolomide, in reducing cell viability and cooperated in reducing cloning efficiency and inducing cell death. With these assumptions, we started a multicentric Phase II clinical trial on newly diagnosed GBM patients with unmethylated MGMT by adding chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol. The experimental procedure involves the combination of CPZ with standard treatment with TMZ in the adjuvant phase of the Stupp protocol. CPZ was administered orally at a dose of 50 mg/day – GG 1-28 – of every cycle of the adjuvant treatment with TMZ. . Efficacy outcomes were evaluated using Kaplan–Meier methodology. OS was measured from diagnosis to death; PFS was determined from radiotherapy to PD or death due to any cause. Between April 2020 and June 2022, 45 patients who met the eligibility requirements were screened. Forty-one patients received at least one cycle of treatment and were included in the analysis. 43 patients have been enrolled, 29 male, 12 female. 20 patients completed 6 cycles of treatment, without relevant toxicity. The results show a median PFS of 8 months (St.Dev. 5,7) and a median OS of 15 months (St.Dev. 6,9). The addition of Chlorpromazine to temozolomide was well tolerated in newly diagnosed Glioblastoma unmethylated patients, with promising impact on outcome measures.
CTNI-48. SURVIVAL, TOXICITY, AND PATIENT REPORTED QOL OUTCOMES FOLLOWING PULSED REDUCED DOSE RATE RE-IRRADIATION WITH CONCURRENT BEVACIZUMAB FOR RECURRENT GRADE 4 GLIOMAS: RESULTS OF A PHASE II STUDY
Authors: Morris Brett , Burr Adam , Weiss Marissa , Anger Nicholas , Harari Colin , Tomé Wolfgang , Bayliss Robert , Bhatia Ankush , Grogan Patrick , Robins Henry , Howard Steven 
Published: November 2023

Abstract
Grade 4 gliomas are aggressive primary brain tumors with dismal prognosis despite maximal treatment. Recurrent disease is typically found within the prior radiation treatment field, complicating reirradiation. Pulsed reduced dose rate (PRDR) radiation is a treatment technique that reduces effective dose rate and increases treatment time allowing for intrafraction repair. Bevacizumab is a systemic VEGF inhibitor with efficacy in treating gliomas. We conducted a phase 2 prospective trial combining PRDR radiation with biweekly bevacizumab (10 mg/kg) in patients with recurrent grade 4 gliomas. Radiation was delivered with reduced dose rate delivered in 20 cGy pulses every 3 minutes in 2 Gy daily fractions to a total dose of 54 Gy. Kaplan Meier analysis was utilized to calculate progression free survival (PFS) and overall survival (OS). Toxicities were evaluated based on Common Terminology Criteria for Adverse Event v5.0 criteria. Mini Mental Status Examination (MMSE), as well as FACT-Brain, and FACIT-Fatigue patient reported quality of life (QoL) surveys were collected at baseline and follow up visits. Minimal important difference scores were calculated using by ½ standard deviation method. A total of 36 patients were enrolled, with 77% having previously received additional therapy for recurrent disease prior to study enrollment. Median PFS was 4.9 months and median OS was 6.9 months. No grade 4+ toxicity was observed. Two patients had grade 3 treatment related toxicity (seizure and radiation necrosis, both PRDR related). Treatment related grade 2 toxicity was seen in 44% of patients, primarily fatigue (30%). Clinically significant decrease in mean MMSE score, and FACT-BR QoL metrics across all sub-domains were noted in follow up. No clinically significant difference in mean FACIT-Fatigue QoL metric was observed. In this prospective phase 2 trial, PRDR with concurrent bevacizumab resulted in encouraging survival outcomes with acceptable toxicity in patients with recurrent grade 4 gliomas.
CTNI-57. PRELIMINARY RESULTS OF A PHASE 1 TRIAL OF ORAL GALLIUM MALTOLATE IN RECURRENT GLIOBLASTOMA
Authors: Connelly Jennifer , Zoss Casey , Schmainda Kathleen , Al-Gizawiy Mona , Pinheiro Fernando Santos , Chitambar Christopher 
Published: November 2023

Abstract

BACKGROUND
Glioblastoma (GBM) is an aggressive brain tumor with a dismal prognosis. New drugs that exploit previously underexplored cancer-related pathways are needed. We and others have shown that GBM stem cells require significantly greater amounts of iron than normal cells to drive critical iron-dependent processes that are altered in malignancy. We showed that oral gallium maltolate (GaM), an iron-targeting metal compound, has significant activity against GBM stem cells in vitro and shrinks GBM tumors and prolongs survival in a rat brain tumor model. GaM’s mechanisms include inhibition of cellular iron homeostasis, ribonucleotide reductase, and mitochondrial complex 1. Further study of GaM’s toxicity and benefit in patients with recurrent GBM is warranted.

METHODS
The Phase 1 trial design follows a 3 + 3 dose escalation scheme. Eligible patients will receive GaM at 3 dose levels: 500, 1,000, or 1,500 mg/day for a minimum of two 28-day cycles. Hepatic, renal, and hematologic functions, iron panel, and gallium levels are monitored every 2 weeks. Toxicity and tumor response are assessed by NCI CTCAE criteria and by RANO criteria, respectively. Patients with responding or stable disease may continue treatment with monitoring.

RESULTS
Ten patients have completed treatment at dose levels 1 and 2 and eight patients are evaluable. Four patients enrolled after first recurrence while the other four patients enrolled after their second, third (2 patients) and fourth recurrence. Median progression-free survival (PFS) on treatment was 118 days. Three patients experienced PFS &gt;180 days and two of those patients remain on treatment. To-date, no dose-limiting toxicities (DLTs) at dose levels 1 and 2 have been encountered.

CONCLUSIONS
Oral GaM is well tolerated without significant DLTs to date. An additional 6 patients are presently enrolled at dose-level 3. Updated toxicity data and clinical outcomes of the study will be presented at the annual SNO meeting.
CTNI-63. A PHASE IIA CLINICAL TRIAL FOR COMBINATION OF NAVIGATION-GUIDE FOCUSED ULTRASOUND AND BEVACIZUMAB FOR PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Wei Kuo-Chen 
Published: November 2023

Abstract

INTRODUCTION
Bevacizumab (BEV), a vascular normalizing therapy that prolongs progression free survival (PFS) for patients with recurrent glioblastoma (rGBM). Focused ultrasound combines with microbubbles (MB-FUS), an emergent technology for targeted blood-brain barrier opening (BBBO), is under investigation for its combinatorial effect with current standard of care for GBM treatment. This study aims to evaluate the safety and efficacy of BEV + MB-FUS for treating patients with rGBM.

METHODS
This is a phase IIa, open-label, single-arm clinical trial (NCT04446416). Eligible patients received BEV (10 mg/kg), then MB-FUS with a MB dosage of 0.1 ml/kg and neuronavigation-guided FUS system (NaviFUS-001, NaviFUS, Taiwan). The MB-FUS is planned to be an add-on modality to the bi-weekly BEV therapy for up to 18 sessions (FUSBEV, 34 weeks).

RESULTS
Six patients underwent total 156 FUS-BEVs (26 times per patients). Three patients (50%) completed the trial protocol, 2 of another 3 patients had disease progression during the treatments, the remaining one patient was in stable disease. The mean progression free survival was 7.5 months. Among the 156 sessions of MB-FUS, there were 3 (1.9%) transient focal scalp pain related to heating. An evaluation of the MB-FUS penetrated regions revealed a significant normalization effect of T2 signal hyperintensity at beam-concentrated areas.

CONCLUSIONS
The PFS-6 was 67% in this study.

RESULTS
have demonstrated the safety, feasibility, and a potential to decrease edema by the mechanism of enhance bevacizumab delivery to the treated site. The preliminary results are encouraging. More data are needed to proof the efficacy of BEV-FUS on rGBM patients.
CTNI-64. EFFICACY AND SAFETY OF ERDAFITINIB IN PATIENTS WITH HIGH-GRADE AND LOW-GRADE GLIOMAS AND PRESPECIFIED FIBROBLAST GROWTH FACTOR RECEPTOR ALTERATIONS (FGFRALT) IN THE RAGNAR TRIAL
Authors: Reardon David , Welsh Liam , Shih Kent , Shimizu Toshio , Goeminne Jean-Charles , Geoerger Birgit , Baldini Capucine , Massard Christophe , Loriot Yohann , Pant Shubham , Sait Sameer Farouk , Thomas Shibu , Hammond Constance , Najmi Saltant , Triantos Spyros , Crow Lauren , Sweiti Hussein , Witt Olaf 
Published: November 2023

Abstract

BACKGROUND
Erda is an oral selective pan-FGFR tyrosine kinase inhibitor approved to treat adults with locally advanced/metastatic urothelial carcinoma with susceptible FGFR3/2alt who have progressed during/after ≥1 line of platinum-based chemotherapy. RAGNAR interim results demonstrated tumor-agnostic efficacy in adults/adolescents with previously-treated advanced solid tumors with prespecified FGFRalt. Here we report results for patients with HGG/LGG.

METHODS
Patients with HGG/LGG harboring prespecified FGFR1-4alt (mutations/fusions), disease progression after ≥1 line of systemic therapy, and who exhausted standard therapies received oral erda until disease progression or intolerable toxicity. Primary endpoint: ORR by independent review committee (IRC). Secondary endpoints: DOR, disease control rate (DCR), investigator-assessed efficacy, and safety. Response was based on RANO criteria.

RESULTS
At data cutoff, 37 HGG (n = 30)/LGG (n = 7) patients received erda. In HGG (glioblastoma, n = 25 [83%]; median (m) age 54.5y [range 13-70]), 29 (97%) had FGFR fusions (FGFR3-TACC3, n = 24); all (100%) underwent initial resection (if feasible) and received radiotherapy/chemotherapy per institution (eg, Stupp protocol); patients received median 2 prior therapies (range 1-6; 37% with prior bevacizumab). ORR in HGG was 10% by IRC (95%CI, 2-27) and 20% by Investigator (95%CI, 8-39); mDOR was not reached (m-F/U, 18.0mo); DCR was 57% (95%CI, 37-75). In LGG (m-age 22y; range 12-32), 4 (57%) had FGFR1 mutation (all FGFR1-K656E); 3 (43%) had FGFR fusion. ORR in LGG was 29% by IRC (95%CI, 4-71) and 14% by Investigator (95%CI, 0-58); mDOR was not reached; DCR was 71% (95%CI, 29-96). 17 HGG patients (57%) had TERT co-alterations; 9 (30%) had PTEN deletions. No HGG/LGG patients had IDH1/2 mutations. Most common (≥40%) adverse events (AEs): hyperphosphatemia, diarrhea, dry skin, dry mouth. 43% had serious AEs (treatment-related, 16%). 19% discontinued due to AEs. No treatment-related deaths occurred.

CONCLUSIONS
Erda demonstrated clinically meaningful activity in heavily pre-treated HGG/LGG with FGFRalt. Safety was consistent with known safety profile of erda.
CTNI-68. PHASE I/II STUDY OF MAINTENANCE THERAPY WITH METFORMIN AND TEMOZOLOMIDE FOR TARGETING GLIOBLASTOMA CANCER STEM CELLS
Authors: Narita Yoshitaka , Ohno Makoto , Kitanaka Chifumi , Tanaka Shota , Sonoda Yukihiko , Mishima Kazuhiko , Ishikawa Eiichi , Ohashi Ken , Nagane Motoo 
Published: November 2023

Abstract

BACKGROUND
Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis. One strategy for overcoming resistance is developing a new therapy targeting the cancer stem/initiating cells. We have shown that the antidiabetic drug metformin (MF) can induce differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation (Stem Cells Transl Med. 2012;1(11)). We conducted a phase I/II study to examine the clinical effect of MF combined with standard maintenance temozolomide (TMZ). Patients and

METHODS
Patients between 20 and 74 years of age with supratentorial GBM were eligible. MF dose-escalation study was performed using a 3 + 3 design as phase I part to determine recommended phase II dose. Dose-limiting toxicities (DLTs) were assessed during the first 6 weeks after MF initiation. After completing phase I study, we proceeded to phase II part.

RESULTS
The first three patients were treated with 1,500 mg/day MF from 2021 and the next four patients were treated with 2,250 mg/day MF, which is the maximum dose approved in Japan. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, which were observed in three patients. All of them were manageable, with grade 1 or 2 (Cancers (Basel). 2022;14(17)). Based on the phase I study, we proceeded to phase II study with 2,250 mg/day MF from April 2022 and finished recruiting patients for phase II part in May 2023. Primary endpoint of phase II trial is progression-free survival rate at 12 months compared to historical data.

CONCLUSION
MF dose of up to 2,250 mg/day combined with maintenance TMZ was well tolerated. We report the safety and efficacy of MF with TMZ for GBM.