bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTIM-20. SYSTEMIC IMMUNE CORRELATES ASSOCIATED WITH LONG-TERM SURVIVAL AFTER THERAPEUTIC ADENOVIRUS (DNX2401) PLUS INTERFERON GAMMA FOR RECURRENT GLIOBLASTOMA EFFECT TRIAL (TARGET): A RANDOMIZED PHASE 1 TRIAL
Authors: Ene Chibawanye , Singh Sanjay , Phillips Lynette , Venkataraman Raja , Puduvalli Vinay , Singh Deep , Tram Nam , Long James , Brady Martin , Raghavan Raghu , Tufaro Frank , Ewald Brett , Anand P J , Bradley Elder J , Fink Karen , Alfred Yung W K , Penas-Prado Marta , Navin Nick , Larman Benjamin , Gomez-Manzano Candelaria , Fueyo-Margareto Juan , Peterkin Joanna , Lang Frederick 
Published: November 2023

Abstract
Anti-tumor immune response following oncolytic virus treatment of glioblastoma may be enhanced by immune activating therapies. Here, in this Phase Ib, multicenter, randomized, open-label study we evaluated the combination of intra-tumoral delivery of oncolytic virus DNX-2401 with subcutaneous interferon gamma (IFN-γ) a T-helper 1 response activator in 37 patients with recurrent glioblastoma. In part 1, 27 patients were randomized 2:1 into DNX-2401 with IFN-γ and DNX-2401 alone with intra-tumoral DNX-2401 administered via a standard biopsy needle. In part 2, 10 patients received intra-tumoral DNX-2401 via an FDA-approved Alcyone MEMS Cannula designed to prevent backflow at high infusion flowrates. DNX-2401 was well tolerated but the addition of IFN- γ was not well tolerated. The primary efficacy endpoint, objective clinical response, was not met. The secondary endpoint of 12-month overall survival for DNX-2401 with IFN-γ, DNX-2401 alone and DNX-2401 via Cannula were 33%, 22%, 0% respectively. The 18-month OS for DNX-2401 with IFN-γ, DNX-2401 alone and DNX-2401 via Cannula were 25%, 9%, 0% respectively. The DNX-2401 with IFN- γ cohort had the most long-term survivors (44.2, 23.7, 20.6 and 20.1 months). Systemic antibody and immune cell profiling following DNX-2401 treatment showed that long term survivors had significantly higher anti-adenovirus specific antibody reactivity and a higher activated CD8+ effector memory T-cell sub-population at 2 months post-treatment relative to baseline. This systemic immune response did not occur in short term survivors following DNX-2401 treatment. Overall, these data suggest that an early and robust systemic adaptive immune response could be used as a biomarker for long term survival following DNX-2401 treatment of recurrent glioblastoma independent of other salvage treatments administered following disease progression during the trial. (Clinical Trial.gov registration: NCT02197169).
CTIM-26. IMPACT ON SURVIVAL OF INTERFERON-ALPHA DELIVERY IN GLIOBLASTOMA WITH UNMETHYLATED MGMT BY IMMUNO-GENE THERAPY WITH TEMFERON
Authors: Finocchiaro Gaetano , Cuccarini Valeria , Gentner Bernhard , Capotondo Alessia , Farina Francesca , Naldini Matteo Maria , Barcella Matteo , Anghileri Elena , Bruzzone Maria Grazia , Carrabba Matteo , D'alessandris Quintino Giorgio , Meco Francesco Di , Ferla Valeria , Franzin Alberto , Ferroli Paolo , Gagliardi Filippo , Legnani Federico , Mazzoleni Stefania , Mortini Pietro , Olivi Alessandro , Pallini Roberto , Patanè Monica , Paterra Rosina , Pollo Bianca , Saini Marco , Snider Silvia , Mullen Karen , Naldini Luigi , Russo Carlo , Ciceri Fabio , Eoli Marica 
Published: November 2023

Abstract
Temferon is an ex vivo gene therapy consisting of autologous Hematopoietic Stem Progenitor Cells (HSPCs) genetically modified with a lentiviral vector to deliver IFN-α2 within the tumor microenvironment by Tie-2 expressing macrophages. TEM-GBM is an open-label, Phase I / IIa dose-escalation study evaluating safety and efficacy of Temferon in up to 27 newly diagnosed GBM patients with unmethylated MGMT (uMGMT). As of 30th April 2023, 19 GBM patients in 4 cohorts received incremental doses of Temferon and four are still alive after a median follow-up of 15 months. Six of the treated patients underwent a second surgical intervention at a median of 11 months after 1st surgery. For all patients, median overall survival (OS) and median progression free survival following first surgery reach 15 months and 9.8 months from diagnosis, respectively. The interim survival rate at 2 years in Temferon-treated patients is 28% (5 of 18 patients; 1 patient excluded as follow-up is below 1 year). OS and survival rate at 2 years of uMGMT patients treated as per the current standard of care (SOC) is 12.7 months and 14,8% respectively. One out of the surviving patients is alive 3 years after first surgery without second line therapy added up to 2 years. The other four patients with 2 year follow-up were treated with Gamma-Knife followed by bevacizumab (n = 1), regorafenib followed by bevacizumab (n = 1) and bevacizumab only (n = 2). Bevacizumab administration started 12 months after 1st surgery for one patient and 19 months for the other 2 patients at 5 mg/kg. These data corroborate the initial evidence on safety and tolerability of Temferon. They also suggest that Temferon has potential to counteract disease progression in patients affected by uMGMT GBM.
CTIM-37. A PILOT STUDY OF AXICABTAGENE CILOLEUCEL (AXI-CEL) FOR THE TREATMENT OF RELAPSED/REFRACTORY PRIMARY AND SECONDARY CENTRAL NERVOUS SYSTEM LYMPHOMA (PCNSL AND SCNSL)
Authors: Nayak Lakshmi , Falvey Caroline , Bouvier Riemke , Chukwueke Ugonma , Hogan Sarah , Kendricken Elizabeth , Meehan Christopher , Redd Robert , Fisher Jennifer , Torres Alexandra , Jones Julia , Lee Eudocia , Kim Austin , Castro Luis Nicolas Gonzalez , McFaline-Figueroa Jose Ricardo , Aquilanti Elisa , Youssef Gilbert , Arrillaga-Romany Isabel , Murakami Mark , Sholl Lynette , Meredith David , Huang Raymond Y , Ramsdell Linda , Gerdemann Ulrike , Keskula Paula , Kaminski Jim , Albanese Alexandre , Bi Wenya Linda , Arnaout Omar , Reardon David , Wen Patrick , Poddar Soumya , Mao Daqin , Mattie Mike , Davis Madison , Filosto Simone , Kean Leslie , Armand Philippe , Jacobson Caron 
Published: November 2023

Abstract

BACKGROUND
Optimal therapy for patients with relapsed/refractory (R/R) CNSL is not defined, and their prognosis is poor. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel(axi-cel) has demonstrated superior efficacy over standard of care in R/R systemic diffuse large B-cell lymphoma and could be an effective regimen for R/R CNSL.

METHODS
This is a pilot study of axi-cel in patients with R/R CNSL. Only corticosteroids were allowed for bridging. Patients underwent lymphodepletion with fludarabine and cyclophosphamide followed by standard axi-cel dosing of 2x106 cells/kg infusion. An Ommaya reservoir was placed prior to infusion. The first 6 patients enrolled were observed for treatment-limiting toxicities(TLTs). The study enrolled a total of 17 patients. Primary endpoint was safety, measured by rate of TLTs and grade 3+ adverse events(AEs). Secondary endpoints included objective response rate(ORR), complete response(CR) rate, duration of response(DOR), progression-free survival(PFS) and overall survival(OS). Exploratory analyses included paired peripheral blood and CSF analyses for axi-cel pharmacokinetics, cytokine levels, flow cytometry, single-cell RNA-Seq and circulating tumor-DNA.

RESULTS
We report the results of all 17 patients(13 PCNSL, 4 SCNSL) enrolled. Median age was 64 years (34-80), 8/17 were women. As of 6/2023, 14 treated patients had &gt;1 month follow-up, with 86%(12/14) ORR and 64%(9/14) CR. Six patients progressed. No TLTs were observed; 15/16(94%) patients developed cytokine release syndrome/CRS (grade 3+, 0%), 8/16(50%) developed immune effector cell-associated neurologic syndrome/ICANS, (grade 3+, 5/16(31%)). PFS, OS, DOR and correlatives will be reported at the meeting. Daily examination of CAR T-cells in blood and CSF by scRNA-Seq revealed evolution of a prominent Type I interferon (IFN) transcriptomic signature of CAR-Ts in the CSF.

CONCLUSION
Axi-cel is safe and well-tolerated in CNSL patients with promising efficacy and no apparent additional risk of adverse neurologic events including ICANS. IFN pathway may play a major role in CAR-T efficacy in CNSL.
CTIM-42. INB-200: PHASE 1 STUDY OF GENE MODIFIED AUTOLOGOUS GAMMA-DELTA (ΓΔ) T CELLS IN NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM) PATIENTS RECEIVING MAINTENANCE TEMOZOLOMIDE (TMZ)
Authors: Lobbous Mina , Goswami Trishna , Lamb Lawrence , Rochlin Kate , Pillay Thiumaine , Youngblood Samantha , ter Haak Mariska , Nabors Burt 
Published: November 2023

Abstract
γδ T cells target NKG2D ligands that are upregulated on tumor cells after chemotherapy exposure. IN8bio’s DeltEx drug resistant immunotherapy (DRI) are γδ T cells genetically engineered to express MGMT, conveying TMZ resistance to allow concomitant therapy. We present updated results from this Phase 1 trial, which enrolled adult newly diagnosed glioblastoma patients with adequate organ function, KPS ≥ 70%. Cohorts (C) 1, 2 and 3 received 1, 3 or 6 doses (1 x 107) of DRI cells intratumorally with 150 mg/m2 of TMZ on Day (D) 1 of Stupp maintenance. The primary endpoint is safety and secondary endpoints include survival; immunologic and genomic correlative analyses are included. Dose limiting toxicities (DLTs) are defined as treatment related ≥ grade (G) 3 cardiopulmonary or hepatic toxicity, G4 toxicity exceeding 72 hours or neurologic deterioration that exceeds 2 weeks. 21 patients were enrolled, with 11 dosing (57% male; median age 68 (range: 21-76); 86% IDH-WT, 52% MGMT unmethylated). No DLTs, cytokine release syndrome (CRS) or neurotoxicity (ICANS) reported. Most common adverse events were WBC/platelet count decreased, asthenia, headache, hydrocephalus, decreased appetite and balance disorder. C1 pts had PFS of 8.3, 11.9, 7.4 months (m) and OS of 15.6, 17.7 and 9.6m, respectively. In C2, 1 pt remains progression free at 26.4m, while one progressed at 22m and another died without relapse at 8.7m. C3 pt had a PFS of 7.1 and OS of 13.11m with other pts in dosing. γδ T cells successfully infused with peripheral TMZ-based lymphodepletion evidenced with near or below normal range T, B, and NK subsets for up to 1 year. DRI T cells have manageable toxicity with encouraging trend in PFS with enriched γδ T cell remaining despite peripheral lymphodepletion.
CTNI-06. RHENIUM (RE-186) OBISBEMEDA{RE-186-NANOLIPOSOME (186RNL)} IN LEPTOMENINGEAL METASTASES [LM] PHASE 1/2A DOSE ESCALATION TRIAL: INITIAL SAFETY AND FEASIBILITY
Authors: Brenner Andrew , Youssef Michael , Kumthekar Priya , Michalek Joel , Hedrick Marc , Bao Ande , Phillips William , Patel Toral , Weinberg Jeffrey , Floyd John , LaFrance Norman 
Published: November 2023

Abstract
CONCLUSIONS: Adjuvant MHT may induce tumor radio-sensitization, immune cell recruitment, and survival benefit when combined with CRT. Optimization of the combination therapy treatment scheme is required.
CTNI-12. GENOMIC ANALYSIS OF HUMAN BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY UNDER THE PHASE-II CLINICAL TRIAL (NCT03398694) REVEALS DNA DAMAGE REPAIR AT THE PERIPHERAL TUMOR EDGE
Authors: Shireman Jack , White Quinn , Agrawal Namita , Ni Zijan , Chen Grace , Mohanty Chitrasen , Zhao Lei , Wang Xiaohu , Ahmed Atique , Miller James , Kulwin Charles , Cohen-Gadol Aaron , Payner Troy , Lin Chih-Ta , Savage Jesse , Lane Brandon , Shiue Kevin , Kamer Aaron , Shah Mitesh , Iyer Gopal , Watson Gordon , Zang Yong , Boyd LaKesha , Lautenschlaeger Tim , Kendziorski Christian , Dey Mahua 
Published: November 2023

Abstract
Stereotactic Radiosurgery (SRS) is one of the leading treatment modalities for oligo brain metastasis (BM), however no comprehensive genomic data assessing the effect of radiation on BM in humans exist. Leveraging a unique opportunity, as part of the clinical trial (NCT03398694), we collected post-SRS, delivered via Gamma-knife or LINAC, tumor samples from core and peripheral-edges of the resected tumor to characterize the genomic effects of overall SRS as well as the SRS delivery modality. Using these rare patient samples, we show that SRS results in significant genomic changes at DNA and RNA levels throughout the tumor. Mutations and expression profiles of peripheral tumor samples indicated interaction with surrounding brain tissue as well as elevated DNA damage repair. Central samples show GSEA enrichment for cellular apoptosis while peripheral samples carried an increase in tumor suppressor mutations. There are also significant differences in the transcriptomic profile at the periphery between Gamma-knife vs LINAC.
CTNI-16. USE OF PREDICTIVE SCORE-BASED HISTORICAL CONTROL DATA IN SINGLE-ARM TRIALS
Authors: Yoo Wonsuk , Kennedy William , Hong Amy , Sanai Nader 
Published: November 2023

Abstract
Even though the randomized controlled trials (RCTs) are still the preferred approach to evaluate the effects of treatments, single-arm study designs have been traditionally used in Phase II oncology clinical trials. The single-arm studies using historical control or external control might be inevitable and even fatal when concurrent controls are impractical or unethical in rare and high-risk diseases. Due to recruiting difficulty, ethical and economic reasons, the single-arm trials can be a good option to test the experimental efficacy with the external control data of historical control rates for early efficacy phase 2 trials in glioblastoma. The FDA guidelines on external control data focus on the use of patient-level data from other clinical trials or real-world data (RWD), and so there is no guidance for summary-level historical control. Furthermore, there exist methodological issues to use historical data like identification of relevant data, amount of discounting (time difference and dissimilarity), prior robustness or operating characteristics. In this study, we propose a synthetic data based predictive scoring method optimally to match the historical control data with the characteristic conditions of the experimental studies. We consider both a binary (PFS on six months) and survival (median PFS) endpoints as surrogates for Phase 2 single-arm trials in newly diagnosed and recurrent glioblastoma patients. We perform meta-analysis to summarize the endpoints and the related socio-demographic, treatment and genetic factors from the summary-level historical data. Then we generate the synthetic patients based on the meta-summarized data. The generalized boosted regression models will be used to identify significant characteristics affecting the survival of GBM patients using the synthetic data. Finally the predictive score-based historical data model will be developed to provide the optimal matching with the characteristics of the experimental studies. This study will be validated using existing patient-level data as well as cross-validation methods.
CTNI-19. RESECTION AND CESIUM-131 RADIATION SOURCES IMBEDDED IN BIO-RESORBABLE COLLAGEN TILES (GAMMATILE™) FOLLOWED BY THE STUPP PROTOCOL IN NEWLY-DIAGNOSED GLIOBLASTOMA: GESTALT TRIAL-IN-PROGRESS UPDATE
Authors: Dunbar Erin , Nowlan Adam , McCracken David , Fink Karen , Lewis Luke , Hoeprich Mark , Lee Stuart , Paravati Anthony , Tuncer Tolga , David John , Mella Divya , Aboud Orwa , Fragoso Ruben , Bloch Orin , Ferreira Clara , Dusenbery Kathryn , Peach Matthew Sean , Chang Eric , Brachman David , Campbell Lisa , Chen Clark 
Published: November 2023

Abstract

OBJECTIVE
To evaluate the safety and feasibility of combining resection with immediate initiation of radiation and subsequent Stupp protocol in newly-diagnosed glioblastoma (GBM).

BACKGROUND
Rapid early local progression (REP) after resection, prior to the initiation of EBRT+/-chemotherapy, occurs in 25-50%. This high-rate of REP supports initiation of an effective postoperative treatment as early as safely possible. Bio-resorbable collagen tiles with imbedded cesium-131 radiation sources (Gammatiles™) are FDA cleared for this use. Intraoperatively, tiles are placed within the resection bed, thus achieving an immediate initiation of surgically targeted radiation therapy (STaRT). DESIGN/

METHODS
GESTALT is a single-arm 61 patient multi-center trial. Consented adults with suspected or confirmed GBM undergo a maximum safe resection with Gammatile™ (STaRT). Patients with molecular GBM (WHO 2021 criteria) start concurrent EBRT/Temozolomide beginning 25±4 days post-surgery. Subsequent EBRT (20 fractions, 4 weeks) to low and high-risk PTV takes Gammatile™ dose into account to a combined biologically equivalent dose of 46 and 60 Gy delivered in 2Gy/fraction, respectively. Adjuvant TMZ (6 cycles) begins 28±7 days after EBRT/Temozolomide. TTF is allowed. IDH-mutated gliomas are followed for safety. Outcomes include feasibility of incorporating Gammatile™ without delay of Stupp protocol, consent/attrition rates, safety, performance status trajectory (ECOG, KPS), immune competence (absolute lymphocyte counts), local control, PFS, and OS.

RESULTS
The trial opened in Fall 2022 at 4 sites. 12 additional sites are onboarding (NCT05342883). 16 patients are on trial as of abstract submission. Currently, this trial appears feasible and without any unexpected intolerances/toxicities.

CONCLUSIONS
This is the first trial in newly diagnosed GBM patients to combine resection, Gammatile™, and the Stupp protocol, in an attempt to reduce REP, as well as possibly, improve other outcomes.

RESULTS
will inform the routine and investigational use of Gammatile™, and if suggestive, will form the basis for a subsequent randomized trial.
CTNI-20. NIMOTUZUMAB COMBINED WITH CONCURRENT CHEMORADIOTHERAPY IN THE TREATMENT OF NEWLY DIAGNOSED PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Qiu Xiaoguang , Jiang Mawei , Liu Chao , Wang Gang , Tao Rongjie , Xu Jiankun , Shen Liangfang , Liu Yanwei , Wang Heling , Zhu Chuanying , Zhang Hui , Zeng Gao , Hong Jidong , Chen Baoshi , Wang Shujun , Bao Wenlan , Yang Jia , Lin Qingtang , Li Huan , Liu Shuai , Zhang Wei , Chen Shuxian , Zhao Yongrui , Tang Jianbing , Kou Zhen , Su Jun , Sun Peng , Wang Longyun , Sun Xiaoyang , Ju Yan , Ma Wenbin , Wang Yu 
Published: November 2023

Abstract

BACKGROUND
Newly diagnosed pediatric DIPG is a fetal disease with a poor prognosis and lacks of effective treatments. Multiple studies have demonstrated that the median survival time for patients is less than one year. A single-armed, prospective, multicenter study was conducted to evaluate the efficacy and safety of adding nimotuzumab to concurrent chemoradiotherapy for the treatment of newly diagnosed pediatric DIPG.

METHODS
Patients were 3-15 years old, histologically or imaging confirmed newly diagnosed DIPG, Lansky score ≥ 60, and at least one measurable lesion. Totally 48 patients were enrolled. Nimotuzumab (150mg/m2/w) concurrent chemoradiotherapy (Temozolomide: 75mg/m2 per day. Radiotherapy: 54Gy/30f) were administered for 6 weeks following a maintenance treatment (Nimotuzumab: 150mg/m2 biweekly. Temozolomide: 150-200mg/m2 per day for 5 days every 28 day). The primary endpoint was ORR, with secondary endpoints including 1-year OS rate, PFS and safety.

RESULTS
Between Apr 3, 2021 and Apr 13, 2023, a total of 48 patients were enrolled with a median age of 7 years old, in which 20 patients radiologically diagnosed DIPG, 28 patients histopathologically confirmed DIPG with 25 (89.3%) had H3K27M mutation. The median follow-up was 15.2 months. The ORR was 31.3% (95%CI, 18.66%-46.25%), mOS was 10.35 months, 1-year OS rate was 27.4% (95%CI, 14.73%-41.73%), mPFS was 6.93 months, and 1-year PFS was 9.5% (95%CI, 2.46%-22.56%). Eight patients (16.7%) experienced grade 3 or above ADRs. The most common toxicities were neutropenia (40%), leukopenia (25.0%), thrombocytopenia (25.0%). anemia (5.0%), flank pain (5.0%).

CONCLUSIONS
Nimotuzumab combined with concurrent chemoradiotherapy showed survival benifit for newly diagnosed pediatric DIPG patients with tolerable toxicity.
CTNI-22. A PHASE 0/2 ‘TRIGGER’ TRIAL OF NIRAPARIB IN PATIENTS WITH NEWLY-DIAGNOSED GLIOBLASTOMA
Authors: Sanai Nader , Margaryan Tigran , Molloy Jennifer , Zhang Hualin , Knight William , Harmon Jocelyn , Hong Amy , Wanebo John , Kennedy William , Braun Kelly , Garcia Michael , Barani Igor , Yoo Wonsuk , Tien An-Chi , Tovmasyan Artak , Mehta Shwetal 
Published: November 2023

Abstract

BACKGROUND
Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients with O6-methylguanine methyltransferase (MGMT) unmethylated tumors into a therapeutic regimen of niraparib plus fractionated radiotherapy when PK threshold is met.

METHODS
Presumed newly-diagnosed GBM patients received 4 days of niraparib (300/200 mg QD) prior to planned resection 3-5 or 8-12 hours following the last dose. Tumor tissue (enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after ex vivo irradiation of surgical vs non-irradiated tissue. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase and was defined as unbound [niraparib] &gt; 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Patients with MGMT unmethylated tumors and positive PK were eligible for phase 2 dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib.

RESULTS
All phase 0 patients (n = 44) met the PK threshold. In non-enhancing tumor regions, the mean unbound concentration of niraparib was 226.7 nM (n = 38). PAR suppression after ex vivo radiation was observed in 71% of the patients (20/28). Eighteen out of 26 patients with unmethylated tumors enrolled in phase 2. Five of the 18 initial patients in phase 2 experienced grade 4 thrombocytopenia related to niraparib. All adverse events were resolved without sequelae. For patients who completed at least 6 months of follow-up, PFS6 was 64% (n = 11) with 9.2-month median follow-up. Median follow-up for all patients (n = 18) was 4.2 months with 8 patients remaining on treatment and 2 patients ongoing PFS6 follow-up.

CONCLUSIONS
Niraparib achieves pharmacologically-relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor.