bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune profiling in patients with glioblastoma treated with VT1021 in a phase I/II expansion study.
Authors: Chen Jian Jennifer , Vincent Melanie , Peereboom David M. , Watnick Randolph , Fyfe Susanne , Li Wendy , Wang Suming , Mahoney James , Cieslewicz Michael , Watnick Jing 
Published: June 2023

2021 Background: The cyclic peptide VT1021 is a first-in-class therapeutic agent that has been shown to inhibit tumor growth via stimulation of thrombospondin-1 (TSP-1) and reprogramming the immune tumor microenvironment (TME) in preclinical models. Subsequently, VT1021 has been tested in a phase I/II clinical study in solid tumors (NCT03364400) and has advanced to a phase II/III clinical study in glioblastoma (NCT03970447). VT1021 has demonstrated promising single-agent clinical activity against recurrent glioblastoma (rGBM) in a phase I/II expansion study. Among 22 evaluable subjects with rGBM, 3 had complete response (CR), 1 had partial response (PR), and 6 had stable disease (SD) with an average study duration of over 120 days. One subject has been on VT1021 treatment for > 900 days with no measurable lesion left. The overall disease control rate (DCR) was 45%. Here, we sought to examine the peripheral immune cell profile(s) in response to VT1021 and explore the association between these profiles and clinical responses in rGBM subjects. Methods: In the phase I/II expansion study, 22 evaluable rGBM subjects received VT1021 at a dose of 11.8 mg/kg (twice per week intravenously) until disease progression. Peripheral blood samples were collected from all evaluable subjects; immune cell profiles were analyzed by flow cytometry. Results: The immune profiles following VT1021 treatment on day 1 did not vary significantly among rGBM subjects, regardless of response. Intriguingly, after long-term VT1021 treatment (day 53), our analysis of the immune profiles revealed beneficial and sustained changes in three cytotoxic T Cell (CTL) parameters and PD-L1+ MDSCs that correlated with response. Specifically, CR/PR subjects showed a 20% increase in total CTLs (Pre 33.79% vs. 6hr 40.42%), a 66% increase in proliferating CTLs (Pre 1.37% vs. 6hr 2.28%) and a 63% increase in CTL/Treg ratio (Pre 7.85 vs. 6hr 12.81) on day 53 of VT1021 treatment. In contrast, SD and PD subjects exhibited no change or decrease in these three CTL parameters, respectively. We also observed that CR/PR subjects experienced a sustained decrease in PD-L1+ MDSCs after VT1021 treatment (day 1 Pre 95.96% vs. day 53 Pre 92.66% and day 53 6hr 88.06%). Conversely, the sustained decrease of PD-L1+ MDSCs after VT1021 treatment was not observed in SD and PD subjects. Conclusions: Here we report that the durable responses of peripheral immune cells to VT1021 may be associated with better clinical outcomes in rGBM subjects. These findings are consistent with the MOA of TSP-1 to reprogram the TME by stimulating immune and inflammatory cell functions. While the interpretation of our data is limited by the lack of a control arm and the small sample size, the results provide a signal and warrant continued analysis of these parameters in the ongoing phase II/III trial.
Ombipepimut dosing emulsion (ODE) + bevacizumab (bev) vs bev alone in patients (pts) with recurrent or progressive glioblastoma (rGBM).
Authors: Goldlust Samuel Aaron , Chang Jong Hee , Narita Yoshitaka , Welch Mary Roberta , Green Richard M. , Drappatz Jan , Piccioni David Eric , Kim Yu Jung , Melear Jason M. , Tanaka Shota , Wei Kuo-Chen , Fink Karen L. , Pitz Marshall W. , Cloughesy Timothy Francis , de Groot John Frederick , McClellan Nanci , Hitron Matthew , Xu Bo , Jin Bo , Lebedinsky Claudia 
Published: June 2023

2022 Background: ODE is an investigational cancer vaccine derived from Wilms tumor 1. WIZARD was a randomized, adaptive, phase 3 study to test ODE + bev vs bev in rGBM pts (NCT03149003). Patients were stratified prior to randomization based upon KPS [60 or 70] vs [80 to 100] and extent of resection at initial diagnosis. Patients with low KPS (e.g., 60) are generally underrepresented in clinical trials. Methods: Pts ≥18 years with GBM at first recurrence were enrolled. Overall survival (OS) was the primary endpoint; the key secondary endpoint was the 12-month OS rate. The primary and the key secondary endpoints were tested using 1-sided test with an overall significance level 2.5%. The Lan-DeMets error spending function based upon O’Brien-Fleming stopping boundaries was used to adjust the significance level for the interim and final analyses. Results: From April 2018 to Aug 2021, 217 pts were randomized 1:1; 109 to ODE + bev and 108 to bev. OS was analyzed after 185 events with a median follow-up of 31.8 months (mo). Pts at baseline had a median age of 60 years, 45.2% reported corticosteroid use, 29% had KPS 60 or 70, 7.8% had tumors that harbored IDH1 or 2 mutations, and the median tumor volume was 10,532 mm3. Baseline characteristics between treatment arms were balanced in the ITT and KPS subgroups. Pts with KPS 60 or 70 had more corticosteroid use, worse NANO scores, and larger tumor burden than those with KPS 80-100. The study did not meet its primary endpoint of OS by ITT (ODE + bev: 10.2 mo vs bev: 9.4 mo, 1-sided p-value: 0.2159). Pts with KPS 60 or 70 had longer OS when treated with ODE + bev (8.2 vs 6.3 mo, 45% death risk reduction, 1-side p value: 0.0119). Grade 1 or 2 injection site reaction was the most common TEAE in the ODE + bev arm. No clinically significant difference in safety was noted between KPS subgroups. Conclusions: The data in pts with KPS 60 or 70 suggested benefit with ODE + bev that was consistent across different endpoints and that warrants further validation. Clinical trial information: NCT03149003 . [Table: see text]
An exploratory clinical trial on intra-lumbar injection of B7H3-specific allogeneic universal CAR-T cells in patients with recurrent high-grade gliomas.
Authors: Shang Xiaoyun 
Published: June 2023

2043 Background: No standard-of-care treatment was established for recurrent high-grade gliomas (rHGGs) yet. Intrathecal infusion of autologous chimeric antigen receptor-T (CAR-T) cells has displayed potent anti-tumor activity in one patient (Brown et al. N Engl J Med 2016). We evaluated the safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of B7H3-specific allogeneic universal CAR-T (B7H3 UCAR-T) cells in patients with rHGGs. Methods: Eligible patients who had received standard treatment for newly-diagnosed high-grade gliomas but failed were treated with 2.5×107 B7H3 UCAR-T cells via intra-lumbar injection every month. Eligibility criteria included histologic and/or cytologic rHGGs, B7H3-positive antigen expression rate of >50% in tumor tissue and Karnofsky performance status (KPS) ≥ 40. The primary endpoint was treatment-related adverse events (TAEs); secondary endpoints include overall survival (OS) and objective response rate (ORR); exploratory endpoints were PK and PD characteristics of B7H3 UCAR-T cells. Results: In the 7 patients enrolled, 4 (57.1%) were female, 5 (71.4%) glioblastoma (WHO Grade IV) and 2 (28.6%) diffuse midline glioma (WHO Grade IV), and the mean age was 40.4 years. The most common reported TAEs were increased cerebrospinal fluid (CSF) IL-6 (7/7, 100%), headache (7/7, 100%), increased blood IL-6 (6/7, 86%) and fever (6/7, 86%). No adverse events of grade 3 or greater related to B7H3 UCAR-T cells were reported. All the adverse events recovered or relieved after treatment. No typical or severe systemic cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) or graft versus host disease (GvHD) were observed during the study period. Based on Immunotherapy Response Assessment in Neuro-Oncology (iRANO), 3 of 7 patients had response to therapy (42.9%; 95% CI: 15.8 to 75.0) and 7 of 7 patients were stable disease (100%; 95% CI: 64.6 to 100). As of cutoff date (January 30, 2023), two patients died. The median OS was not reached (95% CI: 12.9 to could not be estimated). The median follow-up for OS was 15.6 months (95% CI: 14.7 to 16.1). OS rate at 12 months was 85.7% (95% CI: 48.7 to 97.4). The CAR DNA copy numbers increased 1 day after each administration and persist at least 1 month in cerebrospinal fluid. IL-6 concentrations in CSF and peripheral blood increased after each administration while the change and concentration values in peripheral blood were much lower than those in CSF. Conclusions: In patients with rHGGs, B7H3 UCAR-T cells was not associated with any toxic effects of grade 3 or higher. B7H3 UCAR-T cells resulted in a significantly longer overall survival and a higher objective response rate than history data. B7H3 UCAR-T cells persist well in patients. Clinical trial information: ChiCTR2100047968 .
Lisavanbulin in patients with recurrent glioblastoma: Phase 2a results and a consolidated analysis of response-predictive biomarkers.
Authors: Lopez Juanita Suzanne , Haefliger Simon , Plummer Ruth , Clement Paul M. , Laubli Heinz Philipp , Roth Patrick , Evans T.R. Jeffry , Brazil Lucy , Tabatabai Ghazaleh , Wick Antje , Yau Wing Hing Hing , Wunderlich Benjamin , Beebe Kirk , Eisner Joel Robert , Engelhardt Marc , Kaindl Thomas , Lane Heidi A , Hau Peter , Hundsberger Thomas , Steinbach Joachim 
Published: June 2023

2044 Background: Lisavanbulin (BAL101553, prodrug of BAL27862) destabilizes microtubules and promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 is a lipophilic small molecule shown in rodents to penetrate the brain, with antitumor activity in orthotopic glioblastoma (GBM) models. In the Phase 1 part of this study1 (NCT02490800), 2 of 5 patients with recurrent IDH-mutated G4 astrocytoma treated at active dose levels (15–30 mg/day) showed long-lasting objective responses and strong end-binding protein 1 (EB1) expression in GBM tissue by IHC. EB1 is a regulator protein on microtubules. Methods: The objective of the Phase 2 study was to investigate prospectively the response-predictive value of EB1, and to identify RNA-based response signatures in patients with recurrent GBM. A Simon’s two-stage design was used with an objective response rate (ORR) ≥ 2/9 required in Stage 1 to enable a final ORR ≥ 6/19. A prescreening program identified patients with EB1-positive archival GBM tissue. All patients received 25 mg oral lisavanbulin once daily. RNA-seq was performed on archival GBM tissues. Results: GBM tissue samples from 64 of 629 patients (10.2%) obtained from 13 sites in four countries were EB1-positive, and 18 of these patients received lisavanbulin. Of 9 patients with measurable disease evaluable for response in Stage 1, one patient had a partial response, and another had a 44% target lesion area reduction. Despite sustained activity in these patients, formal stage transition criteria were not met, and the study was closed. IHC testing for EB1 did not show sufficient enrichment for response, but it is thought that IDH status may play a role. In addition, RNA-seq analyses identified a five-gene signature that is distinct from expression patterns observed with EB1-IHC positivity, and predicts current responses irrespective of IDH status. This signature is characterized by homeobox gene downregulation, which may be implicated in the control of microtubule dynamics. Conclusions: This Phase 2a study supports previous study results that lisavanbulin is associated with durable responses and clinical benefit in a subset of patients with GBM. RNA-seq analyses of GBM samples suggest further evaluation of the lisavanbulin predictive response signature. 1Lopez et al, JCO 2019;37,15 suppl, 2025. Clinical trial information: NCT02490800 . [Table: see text]
A single-arm, phase 2 clinical trial of abemaciclib in adult patients with recurrent grade 3 oligodendroglioma.
Authors: Bagley Stephen Joseph , Mohan Suyash , Nabavizadeh Seyed Ali , Patel Thara , Prior Timothy , Mansour Maikel , Mccoy Emily , Angeloni Natalie , O'Neill Meghan , Albright Karen , Frangos Suzanne , Blessing Caroline , Coghlan Leah , Maloney Eileen , Desai Arati Suvas 
Published: June 2023

2045 Background: Oligodendroglioma is a malignant glial neoplasm arising primarily in young adults. Although radiotherapy (RT) and chemotherapy result in durable disease control, tumor recurrence is inevitable and life-limiting. The cyclin D1-CDK4 axis is frequently dysregulated in recurrent oligodendroglioma. Abemaciclib is a selective CDK4/6 inhibitor that has been shown to achieve pharmacologically-relevant concentrations in brain tumor tissue. Methods: We conducted a single-center, single-arm, phase 2 trial evaluating the efficacy of abemaciclib in patients with recurrent oligodendroglioma, IDH-mutant and 1p/19q-codeleted, WHO Grade 3, following prior RT and ≥ 1 line of alkylating chemotherapy. Patients received abemaciclib 200mg twice daily. Primary endpoint was progression-free survival status at 6 months (PFS-6). Ten patients were needed for 80% power to detect the difference between the null (PFS-6 = 50%) and alternative (PFS-6 = 85%) hypotheses; one-sided α = 0.05. Modified RANO criteria were used for patients with enhancing tumors and RANO low-grade glioma criteria for patients with nonenhancing tumors. Results: Between November 2019 - August 2022, 10 patients were enrolled (Baseline Characteristics). Most common treatment-related adverse event (trAE) was grade 1-2 diarrhea, occurring in all 10 patients. Grade 3-4 trAEs included grade 4 thrombocytopenia (n=2), grade 3 neutropenia (n=1), grade 3 fatigue (n=2), and grade 3 ALT increase (n=1). In patients with enhancing tumor (n=9), best response was partial response in 2 patients (ORR=22.2%; DOR 13.1 and 7.7 months, respectively), stable disease (SD) in 3 patients (33.3%; duration of SD 17.0, 6.7, and 2.5 months, respectively), progressive disease in 3 patients (33.3%), and not evaluable in 1 patient (11.1%). In the patient with nonenhancing tumor, best response was SD (duration 10.2 months). Median PFS was 7.7 months (95% CI, 1.7 – 13.1 months); median overall survival was not reached (median follow-up 17 months). The study’s primary endpoint was not met; 5/10 patients (50%) were alive and progression-free at 6 months, below the minimum required (8/10) to consider abemaciclib worthy of further investigation. Conclusions: Despite objective responses and durable disease control in a small subset of patients, the efficacy of abemaciclib in recurrent grade 3 oligodendroglioma was not adequate to warrant further clinical evaluation of abemaciclib monotherapy in unselected patients. Correlative studies are ongoing to identify which patients with oligodendroglioma may benefit from abemaciclib. Clinical trial information: NCT03969706 . [Table: see text]
Safety and efficacy of tumor treating fields (TTFields) prior and concomitant to radiotherapy in patients with newly diagnosed glioblastoma: Results from PriCoTTF.
Authors: Kebir Seid , Lazaridis Lazaros , Schmidt Teresa , Oster Christoph , Proescholdt Martin , Hau Peter , Grosu Anca L. , Krex Dietmar , Sure Ulrich , Scheffler Björn , Kleinschnitz Christoph , Pöttgen Christoph , Stuschke Martin , Glas Martin 
Published: June 2023

2050 Background: Tumor Treating Fields (TTFields) therapy is a locoregional, antimitotic cancer modality that utilizes electric fields delivered noninvasively to the tumor region using arrays. Preclinical findings have demonstrated that TTFields have an enhanced inhibitory effect on glioblastoma (GBM) cell proliferation when used concomitantly with radiotherapy (RT). These results provided the rationale for the phase 1/2 PriCoTTF study that investigated the safety and efficacy of TTFields therapy initiated prior and concomitant to radio-chemotherapy in adult patients with newly diagnosed (nd)GBM. Methods: TTFields therapy was initiated following surgery and continued concomitant with radio-chemotherapy and adjuvant chemotherapy for a total of approximately 9 months. TTFields rechallenge was permitted upon GBM recurrence. RT was conducted with arrays placed on the patients’ scalp. The primary endpoint was safety and tolerability gauged by a series of pre-selected treatment-limiting toxicities (TLTs). Results: The baseline characteristics of 33 patients enrolled to date were typical for GBM, except for a small proportion of patients with gross total resection (22.5%). The frequency of adverse events (AEs) grade ≥ 3 was comparable to other studies in GBM. Of note, grade ≥ 3 skin AEs only occurred in 2 patients (6%) and no patients developed a TLT. The median duration of TTFields therapy was 8.4 months. Median overall survival (OS) was not reached (48% of events had occurred), which precluded conclusions regarding efficacy. However, notably, multivariable Cox regression found that OS was independently associated with the number of days patients achieved > 23 h TTFields therapy (HR 0.96, 95% CI 0.93–0.99, P = 0.008). Conclusions: The PriCoTTF study met its primary endpoint by finding that TTFields therapy concomitant with RT was well tolerated in patients with ndGBM. This included that high-grade skin toxicities were rare. Longer follow up is needed to estimate the efficacy of TTFields therapy in this setting, and will need to consider the relatively low overall duration of TTFields therapy and proportion of patients who received GTR.
Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma: The EORTC 1608 STEAM trial.
Authors: Le Rhun Emilie , Gorlia Thierry , Furtner Julia , Felsberg Joerg , Jongen Joost , Maurage Claude-Alain , Ducray Francois , Roth Patrick , Hau Peter , Chinot Olivier L. , Preusser Matthias , Cartalat Stephanie , Van Den Bent Martin J. , Collienne Maike , Reifenberger Guido , Weller Michael 
Published: June 2023

2054 Background: Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor, including CDK-9, that inhibits tumor growth down-stream via depletion of survival proteins such as MCL-1 and MYC. MCL-1 and MYC are frequently overexpressed in glioblastoma. Methods: The EORTC 1608 (NCT03224104) (STEAM) phase 1b trial had a three parallel group (A,B,C) open-label, non-randomized, multicenter design. Groups A and B explored the maximum tolerated dose (MTD) of zotiraciclib in elderly patients (more than 65 years) with IDH1R132H-non-mutant newly diagnosed glioblastoma or anaplastic astrocytoma, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), based on O6-methylguanine DNA methyltransferase promoter methylation status determined centrally. Group C explored single agent activity of zotiraciclib in IDH1R132H-non-mutant glioblastoma or anaplastic astrocytoma at first relapse after temozolomide chemoradiotherapy with a primary endpoint of progression-free survival at 6 months. Secondary objectives included efficacy, quality of life, and safety. Results: The MTD was 150 mg in combination with radiotherapy alone (group A, n=12) or temozolomide alone (group B, n=9) in elderly patients. Two dose-limiting toxicities were observed at 150 mg, one in group A (grade 3 seizure) and one in group B (multiple grade 1 events). Main toxicities included neutropenia, gastro-intestinal disorders, and hepatotoxicity. Progression-free survival at 6 months in group C (n=50) was 6.7%. Conclusions: Zotiraciclib exhibits overlapping toxicity with alkylating agents and low clinical activity as a single agent. Larger randomized trials may be required to explore activity in combination with radiotherapy or temozolomide. Clinical trial information: NCT03224104 .
Prospective phase I study of checkpoint blockade for the treatment of patients with newly diagnosed high-grade glioma prior to radiochemotherapy: Results of nivolumab plus ipilimumab treatment arm.
Authors: Kesari Santosh , Wojcinski Alexandre , Gill Jaya M. , Carrillo Jose Arganda , Wagle Naveed , Nguyen Minhdan , Truong Judy Dang , Juarez Tiffany M. 
Published: June 2023

2057 Background: The limited success of checkpoint inhibitors (CPI) targeting the programmed death-1 (PD-1) axis in the adjuvant setting for glioblastoma has prompted a deeper understanding of the brain tumor and immune microenvironment and evaluating how the sequence of immunotherapy administration impacts antitumor response. We initiated a feasibility study (NCT03425292) of postoperative nivolumab (anti-PD-1) monotherapy and combination therapy in adults with newly diagnosed high-grade gliomas (HGG) prior to radiotherapy. Methods: Within six weeks from surgical resection of newly diagnosed HGG, patients in study Arm 3 received nivolumab 300 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity. The primary endpoint was the rate of dose-limiting toxicities (DLT). Secondary objectives included adverse events, antitumor activity and pharmacodynamic effects of study treatment. Next-generation sequencing (NGS) was performed on archival tumor specimens before treatment and at the time of subsequent surgery. Results: Fifteen patients were treated with nivolumab plus ipilimumab. 27% (4/15) of patients were receiving dexamethasone at treatment initiation. MGMT promoter was methylated in 5 tumors, unmethylated in 9, and equivocal in one. The most common treatment-related adverse events (AEs) were rash, pruritus, fatigue, nausea, and anorexia. Grade 3 AEs were lipase increased (n = 2), anorexia (n = 1), pruritus (n = 1), and rash (n = 3), and Grade 4 cerebral edema occurred in 1 patient. Median progression-free survival (mPFS) was 1.3 months and median overall survival (mOS) was 19.3 months. Paired tumor specimens obtained before and after treatment were analyzed in six patients and revealed molecular changes in response to treatment as well as differences between patients with shrinking tumors versus progressing tumors. Conclusions: We show that nivolumab plus ipilimumab can be safely administered prior to radiation. To our knowledge, this is the first study in which checkpoint blockade therapy was administered for newly diagnosed glioblastoma prior to standard radiotherapy. Despite the short mPFS, mOS was suggestive of a potential long-term benefit from early CPI exposure, and three patients deferred chemoradiation greater than seven months. Analysis of other study arms is ongoing. Clinical trial information: NCT03425292 .