bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-31. AI-GUIDED PERSONALIZED PRECISION RADIATION THERAPY WITH TARGETED DOSE ESCALATION FOR NEWLY DIAGNOSED GLIOBLASTOMA: A MATCHED-CONTROL STUDY
Authors: Akbari Hamed , Mohan Suyash , Kazerooni Anahita Fathi , Rathore Saima , Bilello Michel , Sako Chiharu , Garcia Jose , Jiang Cecilia , Liu Fang , Berger Melanie , Brem Steven , Bakas Spyridon , Mamourian Elizabeth , Pepin Abigail , James Paul , Dorsey Jay , Singh Ashish , Parker Drew , Verma Ragini , Cao Quy , Shinohara Russell T , Bagley Stephen J , Desai Arati , O’Rourke Donald M , Nasrallah MacLean , Alonso-Basanta Michelle , Teo Boon-Keng Kevin , Kurtz Goldie , Shukla Gaurav , Lustig Robert A , Davatzikos Christos 
Published: November 2024

Abstract

BACKGROUND
The purpose of this study was to assess the feasibility and effectiveness of AI-guided personalized precision radiation therapy (PPRT) with targeted dose escalation in enhancing outcomes for patients with newly diagnosed glioblastoma.

METHODS
An open-label trial was conducted at the University of Pennsylvania (NCT03477513) from August 2018 to April 2023, enrolling 20 patients with IDH-wildtype glioblastoma who underwent maximal safe resection. They were matched with a contemporaneous cohort of glioblastoma patients based on age, sex, extent of resection (EOR), O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation status, and IDH status. Propensity score matching (PSM) was employed to select the control group, utilizing one-to-four nearest neighbor matching. One patient was excluded due to concurrent treatment with tumor treating fields (TTFields). The PPRT group received personalized radiation dose escalation to 75 Gy in 30 fractions guided by AI-based predictive modeling of recurrence, along with temozolomide chemotherapy. The control group received standard-of-care chemoradiotherapy, 60 Gy in 30 fractions. A previously published and evaluated (retrospectively and prospectively) predictive AI model, which has demonstrated high predictive value for neoplastic cell infiltration and future tumor recurrence using preoperative, multi-parametric MRIs, was utilized.

RESULTS
Median overall survival was 24.3 months in the PPRT-temozolomide group compared to 17.5 months in the standard-of-care treatment group (hazard ratio [HR]=0.30; 95% CI: 0.16-0.57; p&lt;0.001). Excluding two patients with leptomeningeal disease and bone marrow metastasis, the median survival was 35.4 months (HR=0.25; 95% CI: 0.12-0.51; p&lt;0.001).

CONCLUSION
AI-guided PPRT for newly diagnosed glioblastoma patients demonstrated feasibility in routine clinical practice and significantly improved overall survival compared to matched controls receiving standard-of-care treatment. These findings underscore the potential of personalized precision radiation therapy, with focused dose escalation, in improving outcomes for glioblastoma patients and emphasize the need for prospective validation in a randomized controlled clinical trial.
CTNI-43. MULTI-CENTER PHASE I STUDY OF CONCURRENT PAXALISIB AND RADIATION THERAPY (RT) IN PATIENTS WITH SOLID TUMOR BRAIN METASTASES (BM) OR LEPTOMENINGEAL METASTASES (LM) HARBORING PI3K PATHWAY ALTERATIONS
Authors: Imber Brandon , Kotecha Rupesh , Blau Kathryn , Halasz Lia , Friend John , Young Robert , Offin Michael , Mitchell Ryan , Diamond Eli , Yang Jonathan 
Published: November 2024

Abstract

INTRODUCTION
Partial or whole brain RT is a standard treatment for solid tumor BM and LM. However, tumors harboring PI3K pathway mutations have poorer CNS control after RT alone. Combining RT with paxalisib, a CNS-penetrant PI3K/mTOR inhibitor, may overcome radioresistance.

METHODS
This multi-center, phase I trial (NCT04192981) studied concurrent paxalisib with cranial RT (30Gy in 10 fractions) for PI3K pathway-altered BM/LM. Part A was a 3 + 3 dose escalation cohort of paxalisib at 45, 60 or 75mg to establish maximum tolerated dose (MTD). Part B was an expansion at MTD to further validate safety and early efficacy. CNS response was assessed using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.

RESULTS
From 3/2020-2/2024, 21 patients (median age 58y, n=18 with BM, n=10 with breast cancer) were enrolled. PIK3CA mutations were the most common pathway alteration (n=15, 71%) followed by PTEN deletion (n=3, 14%). Part A enrolled 12 patients of which 9 were evaluable (3 did not complete protocol therapy). There were no dose-limiting toxicities (DLTs) at 45mg, and 2 DLTs at 60mg: grade 3 nausea and grade 4 neutropenic enterocolitis. Subsequently, 9 additional patients were enrolled during Part B at MTD of 45mg, of which 1 withdrew consent prior to completion of study interventions. No additional DLTs were observed during Part B. In total, there were 14 evaluable patients who received 45mg/day paxalisib concurrently with RT, two of whom died of intercurrent extracranial progression prior to CNS restaging. Of the remaining 12, there was robust response signal. At 1-month post-treatment, 6/12 (50%) had partial response (PR) and the remaining had stable disease (SD). To date, best CNS response is 67% PR (8/12) and 33% SD (4/12).

CONCLUSIONS
A MTD of 45 mg/day has been confirmed for paxalisib with concurrent brain RT for PI3K pathway-altered BM/LM. Given significant unmet need, this novel therapeutic combination warrants further investigation given promising activity signal.
CTNI-45. PHASE 2 STUDY OF SORAFENIB, VALPROIC ACID, AND SILDENAFIL IN THE TREATMENT OF RECURRENT HIGH-GRADE GLIOMA
Authors: Shah Palak , Poklepovic Andrew , Tombes Mary Beth , Shrader Ellen , Bandyopadhyay Dipankar , Deng Xiaoyan , Roberts Catherine , Ryan Alison , Hudson Daniel , Sankala Heidi , Kmieciak Maciej , Dent Paul , Malkin Mark 
Published: November 2024

Abstract

PURPOSE
Here we report the results of a single-center phase 2 clinical trial combining sorafenib tosylate, valproic acid, and sildenafil for the treatment of patients with recurrent high-grade glioma.

PATIENTS AND METHODS
Eligible patients were 18 years of age and older with an Eastern Cooperative Oncology Group performance status of 0-2 and pathologically confirmed high-grade glioma (WHO grade 3 or 4), with documented CT or MRI progression or recurrence and measurable or evaluable disease. The treatment schedule was a combination of sorafenib, valproic acid, and sildenafil, each agent administered orally, twice daily continuously. A cycle consisted of 4 weeks.

RESULTS
Clinical toxicities were grade 1 and grade 2, with one grade 3 toxicity for maculopapular rash (6.4%). For all evaluable patients, the median progression-free survival was 3.65 months and overall survival (OS) 10.0 months. There was promising evidence showing clinical activity and benefit. In the 33 evaluable patients, low protein levels of the chaperone GRP78 (HSPA5) was significantly associated with a better OS (p &lt; 0.0026). A correlation between the expression of PDGFRa and OS approached significance (p &lt; 0.0728). Five patients presently have a mean OS of 73.6 months and remain alive.

CONCLUSIONS
This is the first therapeutic intervention glioblastoma trial to significantly associate GRP78 expression to OS. Our data suggest that the combination of sorafenib tosylate, valproic acid, and sildenafil requires additional clinical development in the recurrent glioma population.
CTNI-46. WINDOW-OF-OPPORTUNITY TRIAL OF ULIXERTINIB FOR MAPK-ACTIVATED LOWER GRADE GLIOMAS IN ADULTS
Authors: Majd Nazanin , Kamiya-Matsuoka Carlos , Yuan Ying , Gachimova Evguenia , Wathoo Chetna , Dagher Samir , Chen Melissa , McCutcheon Ian , Slopis John , de Groot John 
Published: November 2024

Abstract
Overexpression of MAPK (Ras-Raf-MEK-ERK) signaling is well known in NF1-associated tumors. MEK inhibition has shown promising results in pediatrics NF1-associated tumors. In addition, we have observed augmented MAPK signaling and anti-tumor activity with MAPK inhibition in preclinical models of CIC-mutated vs. wild-type oligodendroglioma. Ulixertinib is a small molecule inhibitor of ERK that is being developed as a novel anti-cancer drug. A phase I study of ulixertinib in advanced solid malignancies had shown two central nervous system responses. We hypothesized that ulixertinib crosses the blood-brain barrier (BBB) and it will result in improved responses in MAPK-activated lower-grade gliomas in adults (recurrent NF1-mutated gliomas grade 1,2,3 and oligodendrogliomas grade 2,3 which are enriched in CIC-mutation). This is a window-of-opportunity study of ulixertinib in patients ≥18 yo. Twenty patients who are candidates for non-emergent surgical resection will be enrolled (10 in each cohort). Patients will receive neoadjuvant ulixertinib at 600mg BID. Selected patients will undergo CSF collection 1-week after and all will undergo surgical intervention 2-weeks after initiation of ulixertinib. Patients will then continue treatment until disease progression or unacceptable toxicity. Primary endpoints are ulixertinib tumor concentration and tumor/plasma ratio in enhancing and non-enhancing disease. Secondary endpoints include median PFS, overall response rate (ORR) and disease control rate at 12mo, duration of response, time-to-next intervention and time-to-response, safety profile, and ulixertinib CSF and tumor/CSF ratio. Exploratory endpoint includes ORR of plexiform neurofibromas in NF1 patients. To date, 4 patients have been dosed; 3 CIC-mutated oligodendroglioma and 1 NF1-mutated glioma. A fifth patient with NF1-mutated glioma has been consented. Upon collection of tumor tissue on all 5 patients, initial assessment of tumor and CSF drug concentration will be conducted and presented at the conference. Ulixertinib’s ability to cross the BBB could influence what tumor types may be explored for further patient benefit.
CTNI-50. CLINICAL EFFICACY AND PK/PD RESPONSE IN A PHASE 0/2 STUDY OF NIRAPARIB PLUS RADIOTHERAPY FOR NEWLY-DIAGNOSED, MGMT-UNMETHYLATED GLIOBLASTOMA
Authors: Sanai Nader , Umemura Yoshie , Margaryan Tigran , Molloy Jennifer , Zhang Hualin , Knight William , Harmon Jocelyn , Hong Amy , Wanebo John , Braun Kelly , Kennedy William R , Garcia Michael , Barani Igor , Yoo Wonsuk , Tien An-Chi , Tovmasyan Artak , Mehta Shwetal 
Published: November 2024

Abstract

BACKGROUND
Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is a PARP1/2-selective inhibitor. This Phase 0/2 study evaluates tumor pharmacokinetics (PK), pharmacodynamics (PD), and clinical efficacy of niraparib plus fractionated radiotherapy in newly diagnosed, O6-methylguanine methyltransferase (MGMT)-unmethylated glioblastoma (GBM).

METHODS
Newly-diagnosed GBM patients received 4 days of niraparib (300/200 mg QD) prior to planned resection 3-5 (cohort 1) or 8-10 hours (cohort 2) following the last dose. Tumor tissue (gadolinium-enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after ex vivo irradiation vs non-irradiated control. A PK response was defined as unbound [niraparib] &gt; 5-fold biochemical IC50 (19 nM) in non-enhancing tumor. Patients with MGMT-unmethylated tumors and a PK response were eligible for Phase 2 dosing of niraparib plus radiotherapy followed by niraparib monotherapy.

RESULTS
All Phase 0 patients (n=46) met the PK threshold. The mean unbound concentrations of niraparib in non-enhancing tumor regions were 335.1 nM (cohort 1; n=43) and 331.9 nM (cohort 2; n=3). Ex vivo PAR suppression was observed in 73% of the patients (24/33). 71.4% patients with unmethylated tumors were enrolled into Phase 2. Five patients in Phase 2 experienced Grade 4 thrombocytopenia related to niraparib and all adverse events resolved without sequelae. At a mean clinical follow-up of 13.4 months, median overall survival was 20.3 months.

CONCLUSIONS
Niraparib achieves pharmacologically relevant concentrations in non-enhancing, newly-diagnosed GBM tissue. Accompanying PD effects were observed in tumor tissue, no new safety signals were observed, and clinical outcomes were promising. A global Phase 3, open-label, randomized 2-arm study comparing niraparib versus temozolomide in adult patients with newly diagnosed, MGMT-unmethylated glioblastoma is underway.
CTNI-51. A PHASE 0/1 STUDY OF BDTX-1535 IN RECURRENT GLIOBLASTOMA (GBM) PATIENTS WITH EGFR ALTERATIONS OR FUSIONS
Authors: Sanai Nader , Umemura Yoshie , Karapetyan Vahuni , Margaryan Tigran , Huttenlocher Dylan , Harmon Jocelyn , Hong Amy , Yoo Wonsuk , Tien An-Chi , Tovmasyan Artak , Mehta Shwetal 
Published: November 2024

Abstract

BACKGROUND
Alterations to epidermal growth factor receptor (EGFR) occur frequently in high-grade gliomas (HGG) and are critical to its pathogenesis. This Phase 0/1 study evaluates pharmacokinetic (PK), pharmacodynamic (PD), and clinical response to an ATP-competitive, irreversible EGFR inhibitor, BDTX-1535, in recurrent HGG patients with EGFR alterations and/or fusions.

MATERIALS/METHODS
Recurrent HGG patients with EGFR alterations (Arm A) or EGFR fusions (Arm B) received 5 days of BDTX-1535 at 200 mg/daily (cohort 1) or 400 mg/every other day (cohort 2) prior to planned resection at 2-4 hours following the final dose. In the Phase 0 component of the study, total and unbound drug concentrations were measured in tumor tissue (gadolinium (Gd) enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma using validated LC-MS/MS methods. A PK ‘trigger’ was defined as unbound drug concentration above 1 nM and 4.1 nM in Gd non-enhancing tumor in patients with EGFR mutations and amplification, respectively, determined eligibility for Phase 1 therapeutic dosing. PD response was assessed by quantification of percentage of positive pEGFR, pERK and MIB-1 cells in the surgical tumor tissue compared to baseline pre-treatment tissue.

RESULTS
Eleven recurrent HGG patients were enrolled (Arm A, n=11; Arm B, n=0). Mean unbound concentrations of BDTX-1535 in non-enhancing tumor regions were 11.9 nM and 18.8 nM in cohorts 1 and 2, respectively. Eight of nine (88.9%) evaluable patients exceeded the PK threshold and qualified for Phase 1. Suppression of pEGFR and MIB1 was observed in 55% and 67% of patients, respectively. No serious adverse events related to BDTX-1535 were observed. At the time of submission, median PFS and OS have not yet been reached.

CONCLUSIONS
BDTX-1535 is well-tolerated in recurrent HGG patients, achieves pharmacologically relevant concentrations in non-enhancing tumor tissue, and is associated with suppression of EGFR signaling. Efficacy data accompanying this PK/PD response will be reported.
CTNI-53. A GLOBAL, RANDOMIZED, DOUBLE-BLINDED, PHASE 3 STUDY OF VORASIDENIB VERSUS PLACEBO IN PATIENTS WITH ADULT-TYPE DIFFUSE GLIOMA WITH AN IDH1/2 MUTATION (INDIGO): UPDATED EFFICACY RESULTS
Authors: Mellinghoff Ingo K , van den Bent Martin J , Touat Mehdi , Blumenthal Deborah T , Peters Katherine B , Ellingson Benjamin M , Clarke Jennifer L , Mendez Joe , Yust-Katz Shlomit , Mason Warren P , Ducray Francois , Umemura Yoshie , Nabors Burt , Hottinger Andreas F , Arakawa Yoshiki , Sepulveda Juan M , Wick Wolfgang , Soffietti Riccardo , Perry James R , Giglio Pierre , de la Fuente Macarena , Maher Elizabeth A , Tron Adriana E , Zhao Dan , Pandya Shuchi S , Steelman Lori , Hassan Islam , Wen Patrick Y , Cloughesy Timothy F 
Published: November 2024

Abstract

INTRODUCTION
The Phase 3 INDIGO study (NCT04164901) evaluated vorasidenib, an oral, brain-penetrant, dual inhibitor of mutated isocitrate dehydrogenase 1/2 (mIDH1/2), in patients with mIDH1/2 diffuse glioma. The primary endpoint of progression-free survival (PFS) per blinded independent review committee (BIRC), and key secondary endpoint of time to next intervention (TTNI), were met in the positive, preplanned second interim analysis (IA2). The study was unblinded in March 2023 following independent data monitoring committee recommendation. Here, we present results after an additional 6 months of follow-up between the database lock for IA2 (September 6, 2022) and study unblinding (March 7, 2023).

METHODS
Patients with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (≥12 years; Karnofsky Performance Status ≥80; measurable non-enhancing disease; surgery as only prior treatment; no immediate need of chemoradiotherapy). Patients were randomized 1:1 to vorasidenib 40 mg or placebo daily in 28-day cycles.

RESULTS
Overall, 331 patients were randomized (median age: 40.0 years; oligodendroglioma: 172; astrocytoma: 159). As of March 7, 2023, 123/168 (73%) patients remained on vorasidenib and 72/163 (44%) remained on placebo. PFS per BIRC remained in favor of vorasidenib (HR, 0.35; 95% CI, 0.25–0.49), and was consistent with PFS per investigator assessment (HR, 0.34; 95% CI, 0.23–0.50). Median PFS per BIRC: vorasidenib, not estimable (NE; 95% CI, 22.1–NE); placebo, 11.4 months (95% CI, 11.1–13.9). TTNI also remained in favor of vorasidenib (HR, 0.25; 95% CI, 0.16–0.40). Median TTNI: vorasidenib, NE (95% CI, NE–NE); placebo, 20.1 months (95% CI, 17.5–27.1). No new safety signals emerged.

CONCLUSIONS
Vorasidenib is a targeted therapy for patients with predominantly non-enhancing mIDH1/2 diffuse glioma following surgical intervention, as shown in the INDIGO population. These additional 6 months of follow-up confirm the previously reported statistically significant and clinically meaningful improvements in PFS and TTNI with vorasidenib.
CTNI-55. A PHASE 0/1B STUDY OF AZD1390 PLUS RADIOTHERAPY IN NEWLY DIAGNOSED, MGMT-UNMETHYLATED AND RECURRENT GLIOBLASTOMA PATIENTS
Authors: Sanai Nader , Umemura Yoshie , Desai Siddhi , Margaryan Tigran , Molloy Jennifer , LoCascio Costanza , Elliott Mackenna , Harmon Jocelyn , Hong Amy , Melendez Ernesto Luna , Wanebo John , Braun Kelly , Kennedy William R , Garcia Michael , Yoo Wonsuk , Tovmasyan Artak , Tien An-Chi , Mehta Shwetal 
Published: November 2024

Abstract

BACKGROUND
ATM inhibition is hypothesized to potentiate the effects of radiation by preventing acute phase DNA damage repair. This Phase 0/1b study evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of AZD1390, a first-in-class ATM inhibitor, in combination with radiation in newly-diagnosed and recurrent GBM patients (NCT05182905).

METHODS
All patients received 3 days of AZD1390 prior to planned resection at 2-4, 4-6 or 23-25 hrs following the final dose (120/300mg for nGBM and 400mg for rGBM). Tumor tissue, cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. ATM inhibition was assessed via ex vivo tissue radiation, quantifying pRAD50 levels compared to non-radiated control. A PK ‘trigger’ determined eligibility for Phase 1b and patients exceeding the PK threshold (2 nM unbound drug levels in Gd-non-enhancing tumor region) were eligible for therapeutic dosing of AZD1390 plus radiotherapy.

RESULTS
Thirty nGBM patients and twenty-nine rGBM patients were enrolled. Forty-eight out of the forty-nine evaluable patients exceeded the PK threshold and qualified for therapeutic dosing. The mean unbound concentrations of AZD1390 in Gd-nonenhancing tumors of both nGBM and rGBM patients were significantly above the threshold at all dose levels and time intervals. Following 5Gy ex vivo radiation of surgical specimens, pRAD50 expression was significantly suppressed in AZD1390-treated patients compared to untreated controls. To date, 6 MGMT-unmethylated nGBM patients and 15 rGBM patients were enrolled in the Phase 1b component of the study, with median clinical follow-up of 7.0 months. Median PFS and OS have not been reached in the nGBM population. Median OS for rGBM patients was 15.4 months.

CONCLUSION
AZD1390 is well-tolerated in both newly-diagnosed and recurrent GBM patients, achieving pharmacologically relevant concentrations in Gd-nonenhancing tumor tissue, and suppressing radiation-induced increase in pRAD50 levels. These data are the first to demonstrate AZD1390-mediated PD and PK responses in nGBM and rGBM patients. Clinical outcomes data are maturing and will be reported.
CTNI-56. PHASE I STUDY OF VORINOSTAT AND TEMSIROLIMUS IN NEWLY DIAGNOSED OR PROGRESSIVE DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Stitzlein Lea M , Baig Muhammad Usman , Chandra Joya , Mahajan Anita , McGovern Susan L , Paulino Arnold , Andersen Clark R , Gill Jonathan , Von Hertell Leena M , Khatua Soumen , Zaky Wafik 
Published: November 2024

Abstract

BACKGROUND
Diffuse intrinsic pontine glioma (DIPG) carries a poor prognosis with a median survival of less than 12 months. Histone mutation, K27M, and AKT pathway dysregulation play key roles in tumorigenesis. There is no curative treatment with radiation therapy, which currently remains the standard treatment.

METHODS
This is a phase I study of vorinostat and temsirolimus in newly diagnosed (stratum 1) and progressive (stratum 2) DIPG. The primary aims are to determine the safety, maximum tolerated dose, and toxicities (NCT02420613). Stratum 1 received radiation concurrently with vorinostat, followed by vorinostat and temsirolimus for up to 10 cycles. Stratum 2 received vorinostat and temsirolimus for up to 12 cycles. In stratum 1, vorinostat was administered daily at 230 mg/m2. The maintenance phase (both strata) included concurrent vorinostat 230 mg/m2 daily and temsirolimus 25 or 35 mg/m2 (Days 1 and 8).

RESULTS
Six patients were enrolled, three in each stratum. Three of the six patients had confirmed H3 K27M mutations. No dose-limiting toxicity was observed, and most adverse effects were limited to grades 1 or 2, including fatigue, nausea, vomiting, myelosuppression, hyperlipidemia, hyperglycemia, elevated liver enzymes, and creatinine. However, one patient experienced grade 3 leukopenia. Two of the three patients in stratum 1 showed evidence of radiographic response after the chemoradiation phase, of whom one patient had progression-free survival of 12 months and completed the 10 maintenance cycles. All patients at stratum 2 had disease progression with no radiographic response.

CONCLUSION
Overall, the combination of temsirolimus and vorinostat is well tolerated and safe, prompting the need for larger studies to investigate its efficacy. Due to the small number of patients, the study’s findings are limited, and trends in efficacy should be interpreted with caution.