bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-13. A FIRST-IN-HUMAN PHASE 0/1 TRIAL OF 5-AMINOLEVULINIC ACID SONODYNAMIC THERAPY (5-ALA SDT) IN RECURRENT GLIOBLASTOMA
Authors: Sanai Nader , Tien An-Chi , Tovmasyan Artak , Chang Yu-Wei , Margaryan Tigran , Hendrickson Kristen , Eschbacher Jennifer , Yoo Wonsuk , Harmon Jocelyn , Hong Amy , Quarles Christopher , Barani Igor , Alhilali Lea , Mirzadeh Zaman , Mehta Shwetal 
Published: November 2022

Abstract

BACKGROUND
5-ALA SDT is not a blood-brain barrier disruption technique, but rather a first-in-class drug-device therapy exploiting the heme synthesis pathway in recurrent glioblastoma (rGBM). Following IV 5-ALA administration, aberrant tumor metabolism results in protoporphyrin-IX (PpIX) accumulation. Activation of PpIX by non-invasive, non-ablative magnetic resonance-guided focused ultrasound (MRgFUS) induces reactive oxygen species and tumor cell death. This first-in-human Phase 0/1 study investigates the feasibility, safety, and biological effects of 5-ALA SDT in rGBM patients.

METHODS
Six hours prior to SDT, adult patients with rGBM were administered 10mg/kg of an IV formulation of 5-ALA (SONALA-001). Patients were assigned to one of three ascending acoustic energy levels of MRgFUS (200J/400J/800J, measured at transducer surface), followed by a four-day interval prior to planned tumor resection. In each patient, 50% of the enhancing and nonenhancing tumor volume was targeted with MRgFUS with the untreated tumor serving as an internal control. The Optimal Biological Dose (OBD) associated with 5-ALA SDT is the energy level associated with greatest tumor cell death.

RESULTS
8 patients were accrued across all energy levels, and none demonstrated drug- or device-related adverse events. Compared to internal control tissue, the apoptosis biomarker, cleaved caspase-3, was elevated in all patients, but most prominently at the 200J energy level. The oxidative stress biomarkers 4-hydroxynonenal, glutathione, cysteine, and thiol were elevated in treated vs. control tissues at all energy levels. The mean Cmax for 5-ALA and PpIX in plasma were 305 µM and 65 nM, respectively. No off-target histological or radiographic alterations were detected in any patient.

CONCLUSIONS
This first-in-human Phase 0/1 study of a new therapeutic modality for rGBM patients demonstrates that 5-ALA SDT is safe at 200 to 800J and likely induces targeted cell death in rGBM patients via oxidative stress. At 10mg/kg of 5-ALA, the OBD is at or lower than 200J.
CTNI-15. REGORAFENIB IN COMBINATION WITH TEMOZOLOMIDE WITH OR WITHOUT RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED MGMT-METHYLATED, IDH WILDTYPE GLIOBLASTOMA: A PHASE I DOSE-FINDING STUDY (REGOMA-2)
Authors: Padovan Marta , De Salvo Gian Luca , D'Avolio Antonio , Caccese Mario , Zagonel Vittorina , Lombardi Giuseppe 
Published: November 2022

Abstract
Glioblastoma (GBM) has activation of multiple signaling pathways in the tumor microenvironment, including the receptor tyrosine kinases, VEGFR, FGFR and PDGFR. The potential response to anti-angiogenic agents makes GBM an attractive target for regorafenib (REG). Antitumor activity of REG in recurrent GBM patients was shown in the REGOMA trial. Interestingly, in “in vivo” studies, beneficial effects were observed with the combination of REG and temozolomide (TMZ) in subcutaneously xenografts. This phase I open-label multicentric study will evaluate the addition of REG to standard of care treatment with TMZ as adjuvant therapy (cohort A), and in combination with TMZ+RT as concomitant therapy (cohort B), in newly diagnosed MGMT-methylated, IDH wildtype GBM patients. Primary objectives are: to determine the safety and tolerability of REG and to establish the maximum tolerated dose (MTD) of REG in those two cohorts. Secondary objectives are: assessment of pharmacokinetics of REG, TMZ and possible pharmacokinetic interactions between TMZ and REG (cohort A); assessment of preliminary antitumor activity; evaluation of quality of life during the treatment. The dose escalation will be explored according to a “3 + 3” design, starting from cohort A and following 3 dose levels of REG [80 mg, 120 mg and 160 mg; level -1 40 mg will be evaluated in case of Dose-Limiting Toxicity (DLT) during REG 80 mg]. After finding the MTD in cohort A, the cohort B dose escalation will start, exploring escalating oral doses of REG in combination with concomitant TMZ+RT (60 Gy/30 fractions); in the adjuvant phase of cohort B, REG will be given (in association to TMZ) at MTD shown in the prior adjuvant phase dose escalation.The DLT evaluation period will be two cycles from the start of cycle 1 of adjuvant or from day 1 to last day of the concomitant phase. Approximately 36 subjects will be enrolled.
CTNI-16. NRG-RTOG 9802 OBSERVATION ARM - LONG TERM RESULT
Authors: Iwamoto Fabio , Polley Mei-Yin , Shaw Edward , Buckner Jan , Barger Geoffrey , Coons Stephen , Ricci Peter , Gilbert Mark , Brown Paul , Stelzer Keith , Rogers C Leland , Suh John , Schultz Christopher , Howard Steven , Fisher Barbara , Kim Michelle , Huang Jiayi , Haddock Michael , Won Minhee , Mehta Minesh 
Published: November 2022

Abstract

BACKGROUND
Radiation Therapy Oncology Group 9802 was a phase III trial for patients with centrally confirmed LGG (WHO grade II). Participants ³ 40 years or those with neurosurgeon defined less than gross total resection (GTR) were randomized to radiotherapy (RT) +/- PCV. In a separate cohort, adults age &lt; 40 years with neurosurgeon defined GTR were observed by MRI every 6 months without adjuvant therapy. At last report, outcome for the observation cohort was immature with median follow-up of only 4.4 years. Here, we present mature outcomes for the observation arm.

METHODS
Eligible adults (as above) were observed by MRI every 6 months. OS and PFS were estimated by Kaplan-Meier method and estimated hazard ratios to characterize the prognostic variables.

RESULTS
There were 111 eligible patients (median age 30; median KPS = 100). Median follow-up was 16.1 years with 71 (64%) alive at the last follow-up. 79 patients (71%) had progressed with median PFS of 6.9 years. 5, 10, and 15 year-PFS and OS rates were 54%, 39%, 28% and 94%, 77%, and 65%. 1p19q status was codeleted in 32%, IDH1/2 mutant in 78% and MGMT promoter methylated in 39% of tested cases. Multivariate Cox analyses showed that preoperative tumor size ³ 4 cm (HR = 2.43 for PFS, p = 0.001; HR = 2.58 for death, p = 0.016) and residual disease on imaging ³ 1 cm (HR = 2.97 for PFS, P &lt; 0.001; HR = 2.02 for death, p = 0.05) were associated with worse outcomes. Analyses based on molecular results will be presented.

CONCLUSION
A subset of low-grade gliomas can be observed after the initial resection based on younger age, smaller tumor size, and no residual disease on neuroimaging. This can likely be further refined by prognostic molecular markers. Patients with the most favorable prognostic factors can avoid or delay the acute and long-term side effects of RT and chemotherapy for several years.
CTNI-37. REPEATED OPENING OF THE BLOOD-BRAIN BARRIER WITH THE SKULL-IMPLANTABLE SONOCLOUD-9 (SC9) DEVICE: PHASE 1 TRIAL OF NAB-PACLITAXEL AND SC9 IN RECURRENT GLIOBLASTOMA
Authors: Sonabend Adam M , Gould Andrew , Luan Yu , Hou Ye , Kobayashi Mikoto A , Castro Brandyn , Zhang Daniel Y , Chen Li , Korobova Farida , Amidei Christina , Youngblood Mark , Bebawy John Patrick F , Liu Benjamin , Horbinski Craig , Desseaux Carole , Helenowski Irene B , Zhang Hui , Muzzio Miguel , Yue Feng , Canney Michael , Stupp Roger 
Published: November 2022

Abstract

BACKGROUND
The blood-brain barrier (BBB) is a major impediment to pharmacological treatment of gliomas. Low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU/MB), temporarily opens the BBB. Here we investigate the pharmacokinetics and safety of this approach of repeated delivery of albumin-bound paclitaxel (Abraxane®, ABX) to the peri-tumoral brain. To perform LIPU/MB-based BBB opening prior to ABX infusions, we used a novel 6 x 6 cm device with 9 ultrasound emitters (SC9) that is implanted in a skull window after tumor resection.

METHODS
A Phase 1 dose-escalation trial using Bayesian adaptive design was conducted (NCT04528680). Patients with recurrent operable glioblastoma, a WHO PS ≤ 2 and adequate bone marrow and organ function were eligible. After tumor resection and implantation of SC9, repeated cycles of BBB opening by LIPU/MB immediately followed by ABX, was performed every 3 weeks. Intraoperative LIPU/MB and low dose ABX was given prior to tumor resection allowed for investigation tissue concentrations and pharmacokinetics.

RESULTS
Seventeen patients have been treated at six escalating ABX dose levels (40-260 mg/m2). At dose of 260 mg/m2, a grade 3 reversible taxane-associated dose limiting encephalopathy was observed in one patient. The patient continued treatment at a lower dose in subsequent cycles. A second patient exhibited encephalopathy on cycle 2. One patient developed grade 2 cumulative peripheral neuropathy. Intraoperative pharmacokinetic studies showed that ABX tissue concentrations in non-enhancing peri-tumoral brain were increased 3.7-fold after LIPU/MB. sc-RNA-sequencing showed transcriptional dysregulation of membrane transporters, pathways related to trans-cytosis as well as cell-cell and cell-matrix adhesion.

CONCLUSIONS
The LIPU/MB using skull-implantable ultrasound enhances the penetration of ABX in large regions of the brain. The procedure can be performed repeatedly and safely. LIPU-based BBB opening leads to transcriptional alterations in brain endothelium. Funding: NIH/NCI 1R01CA245969-01A1, CarThera (SC9 devices), BMS/Celgene (Abraxane®).
CTNI-60. PRELIMINARY RESULTS OF BINIMETINIB AND ENCORAFENIB IN ADULTS WITH RECURRENT BRAF V600E-MUTATED HIGH-GRADE GLIOMA
Authors: Schreck Karisa , Strowd Roy , Nabors L Burt , Ellingson Ben , Fisher Joy , Desideri Serena , Danda Neeraja , Rudek Michelle , Grossman Stuart , Ye Xiaobu 
Published: November 2022

Abstract

BACKGROUND
Although &lt; 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are being identified more frequently as genetic testing increases in gliomas. Given the treatment-refractory nature HGG, RAF-targeted therapy is of special interest. The combination of encorafenib (BRAF inhibitor) with binimetinib (MEK inhibitor) was evaluated in adults with recurrent BRAFV600-mutated HGG.

METHODS
In this phase 2, open-label, Adult Brain Tumor Consortium trial(NCT03973918) encorafenib (450mg daily) and binimetinib (45mg twice daily) were administered continuously until disease progression, unacceptable toxicity, or death. Eligible patients had a histologically-confirmed HGG with BRAF-V600E mutation identified by PCR or next generation sequencing, and had progressed after radiation and any number of prior medical therapies. The primary endpoint was radiographic response rate by RANO criteria. Plasma was collected at baseline, on-study, and at progression for correlatives.

RESULTS
Five patients enrolled between January 2020 and November 2021. All patients had at least one prior recurrence (range 1-4) and received radiation one or more times. Median age was 27 years(range 22-77). Histopathologic diagnosis was glioblastoma(n = 2), anaplastic PXA(aPXA; n = 2), and anaplastic ganglioglioma(aGG; n = 1). Patients received treatment for 2-28months; currently 2/5 patients remain on treatment (8 and 30 months). Radiographic response rate was 60%(3/5): CR in two (glioblastoma, treated 10months; glioblastoma, 8months treatment ongoing), PR in one (aPXA, 28months treatment ongoing), SD in one (aGG, treated 3months), and PD in one (aPXA, treated 2months). Likely attributable adverse events (CTCAE grade ≥ 3) included cilioretinal artery occlusion (came off study) and asymptomatic elevated CPK. Analysis of paired plasma samples and correlation with response is ongoing.

CONCLUSIONS
Encorafenib and binimetinib demonstrate promising tumor responses in patients with recurrent BRAFV600E-mutated HGG with sustained responses in all GBM and 50% of aPXA in this small series, warranting careful consideration in this rare tumor subgroup. This Phase 2 study has closed due to enrollment issues
CTNI-65. INTUITT-NF2, AN ADAPTIVE PLATFORM-BASKET TRIAL FOR NEUROFIBROMATOSIS 2 PATIENTS WITH PROGRESSIVE TUMORS: INTERIM RESULTS OF THE BRIGATINIB TREATMENT ARM
Authors: Plotkin Scott , Allen Jeffrey , Babovic-Vuksanovic Dusica , Dinh Christine , Nghiemphu Leia , Trippa Lorenzo , Yohay Kaleb , Blakeley Jaishri 
Published: November 2022

Abstract
Neurofibromatosis type 2 (NF2) predisposes affected individuals to vestibular schwannomas (VS), non-vestibular schwannomas (NVS), meningiomas, and ependymomas. We developed an adaptive platform-basket trial to screen multiple drugs against any type of progressive NF2-related tumor. We report the interim analysis of the first treatment arm with brigatinib, an ALK inhibitor that inhibits multiple tyrosine kinases. We conducted a multicenter, phase II, open-label study for subjects ≥12 years old with NF2 and progressive target tumors (baskets: VS, NVS, meningioma, or ependymoma). Up to 5 non-target tumors were followed in each participant. In stage 1, 20 participants (minimum of 2 participants per basket) were treated with brigatinib 180 mg daily. Tumor response was evaluated by MRI every 3 months in year 1 and every 6 months thereafter. Radiographic response (RR) was defined as ≥20% decrease in target tumor volume from baseline. The primary outcome was RR rate. Per protocol, the brigatinib arm would be discontinued if no target tumor achieved a RR at interim analysis. Twenty subjects (median age=25 years, 7 pediatric, 12 females) were treated. Target tumors included 10 VS, 3 NVS, 5 meningiomas, and 2 ependymomas; non-target tumors included 18 VS, 36 NVS, and 14 meningiomas. RR rate for target and non-target tumors was 5% and 22%, respectively. By tumor basket, RR was 28% for meningioma, 26% for non-VS, 4% for VS, and 0% for ependymomas. Annualized tumor growth rates decreased for VS, NVS, and meningioma during treatment. Brigatinib was well tolerated with one dose reduction and one discontinuation due to grade 2 diarrhea. Brigatinib treatment was associated with RR in meningiomas, VS, and NVS. In stage 2, the study will enroll 20 participants in the two most promising baskets (meningioma and NVS). This novel design provides unique ability to assess treatments for hereditary syndromes with multiple primary tumors.
CTNI-66. THE PREOPERATIVE BRAIN IRRADIATION IN GLIOBLASTOMA (POBIG) STUDY: A NOVEL TREATMENT PARADIGM TO IMPROVE OUTCOMES?
Authors: Borst Gerben , Waqar Mueez , McBain Catherine , Beasley William , Golby Christopher , Hamerlik Petra , Karabatsou Tina , Bailey Matthew , D’Urso Pietro , Djoukhadar Ibrahim , Akkari Leila , Richardson Jenny , Hewitt Lauren , DuPlessis Daniel , O’Leary Claire , Jackson Richard , Coope David , Roncaroli Federico 
Published: November 2022

Abstract

OBJECTIVE
The Preoperative Brain Irradiation in Glioblastoma (POBIG) study evaluates for the first time the safety, feasibility, and impact of single fraction preoperative radiotherapy in newly diagnosed glioblastoma patients.

METHODS
Operable patients with a radiological diagnosis of glioblastoma, by consensus of a multidisciplinary tumor board including two dedicated neuro-radiologists, are screened for the study. Anatomical and functional MRI sequences are acquired for further tumor characterization and preoperative radiotherapy planning. Radiotherapy is delivered approximately two weeks after the initial screening. Radiation targets the macroscopic and microscopic tumor region at risk of being left behind during surgery and spares at least 2cc tumor volume being debulked to safeguard unperturbed and clinically relevant tissue examination and molecular profiling. The study dose-escalates (from 8Gy to 14Gy) based on the time-to-event Continual Reassessment Methodology. Subsequently, patients undergo surgical debulking followed by postoperative fractionated radiotherapy 60Gy/30fr with concurrent temozolomide.

RESULTS
The first POBIG study patient underwent preoperative radiotherapy followed by a subtotal resection of a left posterior fronto-opercular tumor and completed the postoperative chemoradiotherapy. Screening, study consent, MRI imaging and analysis, radiotherapy planning and delivery until surgery can be achieved within three weeks from screening while maintaining adequate and personalized patient communication. There were no surgical or radiotherapy delays or complications. During surgery, we successfully sampled unirradiated and irradiated tumor regions. The radiotherapy field covered the whole remnant tumor, and image-guided obtained tumor samples and imaging analysis showed clear evidence of differential radiation-induced changes.

CONCLUSION
We successfully initiated a new treatment strategy of preoperative radiotherapy for glioblastoma patients. The first patient completed the treatment, and the study is now open for further recruitment. Paired tumor sampling and advanced imaging analysis showed promising results. The POBIG study offers a unique opportunity for a paradigm shift towards personalized treatment regimens, hopefully leading to better outcomes.
CTNI-68. FIREFLY-1 (PNOC026): PHASE 2 STUDY OF PAN-RAF INHIBITOR TOVORAFENIB IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH RAF-ALTERED RECURRENT OR PROGRESSIVE LOW-GRADE GLIOMA OR ADVANCED SOLID TUMORS
Authors: Kilburn Lindsay , Landi Daniel , Leary Sarah , Ziegler David , Baxter Patricia , Franson Andrea , McCowage Geoffrey , Waanders Angela , Van der Lugt Jasper , Oren Michal Yalon , Gerber Nicolas , Gottardo Nicholas , Khuong-Quang Dong-Anh , Nysom Karsten , Bailey Simon , Driever Pablo Hernáiz , Perreault Sebastien , Witt Olaf , Hahn Seungmin , Hargrave Darren , Hassall Timothy , Jabado Nada , Kang Hyoung Jin , Larouche Valerie , Toledano Helen , Kline Cassie , Abdelbaki Mohamed , Chi Susan , Gardner Sharon , Whipple Nicholas , Mueller Sabine , Blackman Samuel , Zhao Xin , Da Costa Daniel , Cox Michael , Packer Roger , Hansford Jordan 
Published: November 2022

Abstract

BACKGROUND
RAF alterations are oncogenic drivers found in most pediatric low-grade gliomas (LGGs). Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor.

METHODS
FIREFLY-1 (NCT04775485) is a multicenter phase 2 study evaluating the safety and efficacy of tovorafenib monotherapy. Registrational arm 1 enrolled patients with recurrent/progressive LGG harboring an activating BRAF alteration. Patients aged 6 months–25 years who progressed following ≥ 1 prior line of systemic therapy were eligible. Tovorafenib 420 mg/m2 (≤ 600 mg) was administered weekly (tablet or liquid suspension formulation) until progression or for ≥ 26, 28-day cycles. The primary endpoint (arm 1) was overall response rate, as defined by RANO criteria, per independent review.

RESULTS
As of April 14, 2022, 25 patients were enrolled to arm 1 and had ≥ 6 months of follow-up. Median age at enrollment was 8 years (range 3–18). Most patients had astrocytomas (92%), 48% with optic pathway involvement. Patients were heavily pretreated (56% with ≥ 3 prior lines of therapy), and 72% previously received MAPK pathway-targeted agents. Tumors harbored BRAF fusions (84%) or BRAF V600E mutations (16%). Per independent assessment, partial responses (1 unconfirmed) were seen in 14 (64%) of 22 evaluable patients, with 6 additional patients having stable disease, and a clinical benefit rate of 91%. Responses were achieved in tumors with BRAF fusions and V600E mutations. Most treatment-emergent adverse events (AEs) were grade 1 or 2 (96%). The most common grade ≥ 3 AEs were anemia (12%), vomiting, increased blood creatinine phosphokinase and maculopapular rash (8% each). Seven patients (28%) required dose modification for treatment-related AEs; no patients discontinued tovorafenib due to AEs. Updated results, including efficacy per RAPNO assessments will be presented.

CONCLUSIONS
Tovorafenib was generally well tolerated and showed encouraging evidence of antitumor activity in children with pretreated BRAF-altered LGG.
DDEL-09. FRACTIONATED INTRACAVITARY RADIOIMMUNOTHERAPY WITH LU-177 LABELED 6A10 FAB FRAGMENTS IN PATIENTS WITH GLIOBLASTOMA
Authors: Müther Michael , Roll Wolfgang , Böning Guido , Delker Astrid , Zeidler Reinhard , Gildehaus Franz Josef , Stegger Lars , Schäfers Michael , Reulen Hans-Jürgen , Stummer Walter 
Published: November 2022

Abstract

Background
Radio-immunotherapy (RIT) with Lu- 177 labeled 6A10-Fab fragments, targeting tumor-associated carbonic anhydrase XII (CA12) and applied directly into the resection cavity, offers a promising strategy to address hibernating tumor burden after resection and completion of adjuvant treatment for glioblastoma. We report on the first in human applications.

METHODS
Three patients underwent microsurgical resection of glioblastoma. After completion of adjuvant radio- and chemotherapy, RIT was offered in a compassionate use setting. After implantation of an injection reservoir into the tumor cavity, three consecutive doses of Lu-177 labeled 6A10 Fab fragments were administered over three months, corresponding to 25% - 50% - 25% of the total activity. The injected dose was adapted to the size of the resection cavity. Dosimetry was performed with planar whole-body scintigraphy and SPECT/CT 12h, 24h, 48h, 76h and 5-7 days after injection.

RESULTS
Patient 1 (IDH1-Mutation) received three doses of RIT (total of 592 MBq) with stable disease 12 months after therapy and 26 months after initial diagnosis. Patient 2(IDH-Wildtype) had histologically proven tumor progression after the second cycle (total of 526 MBq). Patient 3 (IDH-Wildtype) has so far received one cycle of RIT (327 MBq of a planned total of 1300 MBq). No toxicity according to CTCAE version 6.0 or other adverse events related to RIT were observed. Dosimetry did not reveal absorbed doses above the upper dose limits for organs at risk.

Conclusions
Intracavitary radioimmunotherapy with Lu-177 labeled 6A10-Fab fragments appears to be a safe maintenance therapy for glioblastoma patients, albeit only assessed in three compassionate use situations far. A multicenter confirmatory phase-I-trial will be was initiated in May 2022 (EudraCT-No: 2015-004417-25) to determine the maximum tolerated dose and safety of adjuvant RIT with Lu-177 labeled 6A10-Fab fragments.