bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-58. A PHASE 0/2 TRIAL OF ABEMACICLIB PLUS LY3214996 IN RECURRENT GLIOBLASTOMA
Authors: Sanai Nader , Umemura Yoshie , Chang Yu-Wei , Margaryan Tigran , DeSantis Anita , Elliott Mackenna , Molloy Jennifer , Huttenlocher Dylan , Hook Garry , Yoo Wonsuk , Tien An-Chi , Tovmasyan Artak , Mehta Shwetal 
Published: November 2024

Abstract

BACKGROUND
This Phase 0/2 study (NCT04391595) evaluates tumor pharmacokinetics (PK), tumor pharmacodynamics (PD), and clinical efficacy of abemaciclib, a CDK4 and 6 inhibitor, plus LY3214996, an ERK 1/2 inhibitor, in recurrent glioblastoma (rGBM).

METHODS
Adult rGBM patients (n=42) with intact RB, &gt;30% pERK expression, and CDKN2A/B deletion or CDK4/6 amplification received six days of abemaciclib plus LY3214996 prior to a planned resection. Time-escalation cohorts (3-5 and 7-9 hour intervals from last dose to tumor resection) identified the optimal time interval (OTI). Subsequent Phase 0 patients had tumor tissue (gadolinium [Gd]-enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma collected at the OTI. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. Tumor PD was compared to matched archival or pre-treatment biopsied tissue. A PK ‘trigger’ (i.e., unbound concentration &gt; 5 x IC50) was set for each drug. Gd-nonenhancing tumor demonstrating PK response to both drugs qualified patients for the Phase 2 component of the study.

RESULTS
Forty two patients were accrued to Phase 0 and no dose-limiting toxicities were observed. Median unbound concentrations in Gd-nonenhancing tumor regions were 31 nM and 10 nM for abemaciclib and LY3214996, respectively. Tumor RB, RSK phosphorylation, and tumor proliferation (MIB-1) decreased in (47.5%), (25%) and (72.5%) patients, respectively. Nine of the 40 (22.5%) patients exceeded PK thresholds for both abemaciclib (12 nM) and LY3214996 (25 nM), qualifying them for Phase 2. Here, median PFS and median OS were 2.4 and 7.2 months, respectively.

CONCLUSION
Abemaciclib and LY3214996 achieved pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue in 80% and 30% of the patients, respectively. Suppression of the RB pathway and tumor proliferation, but not ERK pathway was observed. Inadequate CNS penetration and tumor PD modulation by LY3214996 contributed to the unremarkable clinical efficacy profile of this drug combination. Targeted ERK inhibition remains an unmet need in experimental GBM therapy.
CTNI-64. TRIAL IN PROGRESS: DIET2TREAT -- A RANDOMIZED MULTICENTER PHASE 2 TRIAL OF A KETOGENIC DIET VS STANDARD DIETARY GUIDANCE IN COMBINATION WITH STANDARD-OF-CARE TREATMENT FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Amaral L J , Gresham Gillian , Butowski Nicholas , Peters Katherine , Sharma Akanksha , Fonkem Ekokobe , Chi Jen-Tsan , Lin Pao-Hwa , Kesari Santosh , Shiao Stephen , Tighiouart Mourad , You Sungyong , Rudnick Jeremy , Freedland Stephen , Hu Jethro 
Published: November 2024

Abstract

BACKGROUND
Many glioblastoma (GBM) patients inquire about the potential therapeutic benefits of a high fat / low carbohydrate ketogenic diet (KD). Preclinical models and early-phase trials have shown encouraging results, but definitive evidence of clinical efficacy is lacking.

METHODS
We are conducting a multicenter randomized controlled phase 2 clinical trial (NCT05708352) of KD vs standard dietary guidance (SD) for patients with newly diagnosed GBM. All patients receive standard-of-care chemoradiation. Inclusion criteria: newly diagnosed GBM, age ≥ 18 years, Karnofsky Performance Status ≥ 70. Exclusion criteria: inability to wean steroids below 8 mg dexamethasone/day, Body Mass Index &lt; 21 kg/m2, food preferences incompatible with KD. Patients are randomized 1:1 to implement either KD or SD for a study period of 18 weeks, starting alongside chemoradiation. The primary outcome is overall survival for patients randomized to the KD arm compared to those randomized to the SD arm. Secondary outcomes include progression-free survival, health-related quality-of-life (FACT-BR, FACIT-F), cognitive performance (HVLT-R, Trail-Making Test A/B), and physical activity (modified Godin leisure questionnaire, continuous activity monitoring (Fitbit)). Patients randomized to the KD arm will be provided a fingerstick monitor to check blood ketone and glucose levels twice daily. Glucose and ketone levels are also periodically monitored for patients on the SD arm. Blood, tumor, and stool samples are being collected for high throughput profiling to assess the effects of KD on metabolic markers and immune response. Target accrual is 170 patients over 5 years. Enrollment began in July 2023 and is ongoing. As of May 2024, the trial is open for enrollment at Cedars-Sinai and UCSF, and will be opening soon at Duke, St. John’s Cancer Institute, and the Medical College of Wisconsin. 13 patients have been randomized to date. Funding provided by NIH R01CA276919 and the Foundation for Metabolic Cancer Therapies.
CTNI-68. UPDATES ON A POTENTIALLY PIVOTAL TRIAL CNS-201: A RANDOMIZED, CONTROLLED TRIAL OF BERUBICIN VS. LOMUSTINE AFTER FIRST-LINE THERAPY FOR GLIOBLASTOMA MULTIFORME (GBM)
Authors: Silberman Sandra , Muzyczenko Zena 
Published: November 2024

Abstract
Berubicin, derived from doxorubicin (Dox), appears to cross the BBB and has shown significant central nervous system (CNS) uptake and anti-tumor activity. A current, potentially pivotal trial for patients with recurrent GBM after first-line therapy has completed enrollment in the US and Europe: a total of 252 patients were randomized 2:1 (Berubicin:Lomustine) after failure of prior therapy. All patients had to have certification of progression by a central reader, were Grade 4 IDH WT, and were stratified by MGMT methylation status. The primary endpoint, overall survival (OS), is maturing in this blinded trial; however, data will be presented that will document the demographics of the Berubicin and Lomustine arms, and provide a comparison of safety profiles and disposition of the patients enrolled on the study. Recently, a pre-planned non-binding futility analysis of the primary endpoint, OS, was evaluated when the trial reached ~30% of expected events (44 events). This interim analysis was performed by an independent statistician under the supervision of the Data Safety Monitoring Board (DSMB), which was additionally comprised of two oncologists. The DSMB’s charter mandated that they review the primary endpoint, OS, as well as secondary endpoints and safety data to determine whether these data for the risk-benefit profile warranted modification or discontinuation of the study. The DSMB recommended that the study continue as it was currently planned, with no modifications required, having met a pre-determined conditional endpoint. After the results of this interim analysis, CNS Pharmaceuticals completed enrollment with 252 patients evaluable for efficacy based on OS evaluations. Based on the decision of the DSMB, as well as the data presented herein, which includes comparative safety and balanced randomization of the arms, we will provide our recommendations and highlight our further development of Berubicin as a therapeutic option for patients with recurrent GBM as well as other CNS malignancies.
CTNI-70. RESULTS FROM THE PHASE 1 AND PHASE 1 EXPANSION COHORTS OF SJ901: A PHASE 1/2 TRIAL OF SINGLE-AGENT MIRDAMETINIB (PD-0325901) IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH LOW-GRADE GLIOMA
Authors: Robinson Giles , Vinitsky Anna , Bag Asim , Chiang Jason , Li Qian , Lin Tong , Hoehn Mary Ellen , Edwards Angela , Storment Diana , Singh Anjali , Larkin Jennifer , Freeman Jana , Pranica Johanna , Bertrand Kelsey , Bagchi Aditi , Qaddoumi Ibrahim , Moreira Daniel , Baughman Todd , Hoang Thuy , Shearer Todd 
Published: November 2024

Abstract

BACKGROUND
Mirdametinib is an investigational, oral, selective MEK1/2 inhibitor (MEKi) with high blood-brain-barrier penetration. We hypothesized that mirdametinib would benefit patients with pediatric low-grade gliomas (pLGG) and launched SJ901 (NCT04923126) to determine the recommended Phase 2 dose (RP2D), safety, and efficacy.

METHODS
For Phase 1 and Phase 1 expansion patients were required to be ≥2 and &lt;25 years-old, MEKi-naive, and have recurrent/progressive pLGG with biopsy-proven MAPK pathway activation (except BRAF V600). Three dose levels (DL1: 2 mg/m2/dose BID, DL2: 2.5mg/m2/dose BID, DL3: 3mg/m2/dose BID administered continuously in 28-day cycles) were evaluated with an expansion cohort to assess the highest tolerated dose level in a total of 12 patients. RP2D was defined as the dose causing ≤3 dose-limiting toxicities (DLTs) in 12 patients within the first cycle of therapy.

RESULTS
Between June 2021 and December 2023, 23 patients enrolled (DL1=5, DL2=6, and DL3=12). Median age was 8.4 years (2.5-21.9); 52% female. Alterations were seen in BRAF (n=12;52%), FGFR1 (n=5;22%), NF1 (n=3;13%), RAF1 (n=2;9%), and MYB (n=1;4%). The median follow-up time was 14.6 months (3.2-27.8). One DLT was observed (grade-3 thrombocytopenia). Seventeen (74%) patients completed or remain on-therapy; 4(17%) stopped for progression (2 FGFR1; 1 MYB; 1 BRAF); 2 discontinued for toxicities [1 grade-2 rash; 1 grade-4 creatine phosphokinase (CPK) elevation]. Dose modifying adverse events included weight gain, CPK elevations, and rash. No significant cardiac or retinal toxicity was observed. Twelve (63%) of 19 patients with measurable tumors achieved an objective response (1 major, 6 partial, 5 minor). The median time to ≥ minor response was 5.4 months (1.7-7.3). DL3 (3 mg/m2/dose BID) was declared the RP2D.

CONCLUSIONS
Mirdametinib is well-tolerated and has promising clinical activity in patients with recurrent/progressive pLGG. Phase 2 is ongoing to establish safety and efficacy in newly diagnosed, recurrent/refractory tumors, and in patients with prior MEKi exposure.
CTNI-71. RELA FUSION-POSITIVE EPENDYMOMA, DIFFUSE MIDLINE GLIOMA AND GRADE 4 IDH MUTANT ASTROCYTOMA TREATED WITH VAL-083 UNDER EXPANDED ACCESS: CASE REPORTS
Authors: Kamiya-Matsuoka Carlos , Weathers Shaio-Pei , Knight Stephanie , Hanna Teresa , Langlands John , Brown Dennis , Puduvalli Vinay 
Published: November 2024

Abstract
RELA fusion-positive ependymoma is associated with supratentorial location, higher WHO grade and poor prognosis. Diffuse Midline Glioma (DMG) is a relatively rare CNS tumor, originating in the midline location of the brain. Surgical intervention is restricted to biopsy and radiation. Grade-4 astrocytoma, is highly aggressive with rapid progression. Standard treatment includes surgery and radiation therapy, with limited systemic options other than clinical trials for recurrent disease. VAL-083 is a DNA-targeting agent which rapidly induces inter-strand DNA cross-links at O6- and N7-guanine inducing double-strand breaks causing cell death and acts independent of MGMT DNA repair in high-grade gliomas. We report on 4 patients who had recent disease progression and unmethylated MGMT promoter status treated with VAL-083 under an expanded access program: Case #1: a 47-yo male diagnosed with IDHwt, RELA fusion-positive ependymoma. Case #2: an 18-yo male diagnosed with IDHwt, MAP2K1 and RELA fusion-positive ependymoma. Case #3: a 25-yo male diagnosed with IDHmut Grade 4 astrocytoma, with ATRX, INPP4A, RET and TP53 mutations. Case #4: a 21 yo male diagnosed with IDHwt DMG of the brain stem. All patients had multiple recurrences, received radiation and multiple systemic treatment regimens. They received VAL-083 (30 mg/m2 for 3 days every 21 days) under an expanded access program. Patients with ependymoma received 6 and 5 cycles of VAL-083, (case 1 and 2, respectively), while the patients with IDHmut Gr 4. astrocytoma and DMG received 5 and 18 cycles of VAL-083, respectively. No adverse events were reported and no dose reductions were required. These cases highlight that VAL-83 may be a treatment option for recurrent RELA fusion-positive ependymoma, Gr4. IDHmut astrocytoma, and DMG refractory to other treatment regimens. Additional outcomes related to these cases will be presented at the meeting. Clinicaltrials.gov Identifier: NCT03138629. The treatment plans for the EA patients were approved by MD Anderson Cancer Center IRB
CTNI-74. SONODYNAMIC THERAPY (SDT) USING INTRAVENOUS 5-AMINOLEVULINIC ACID WITH NON-ABLATIVE FOCUSED ULTRASOUND FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMAS IN PEDIATRICS: INITIAL SAFETY AND OUTCOMES THE MULTICENTER SDT-201 TRIAL
Authors: Kilburn Lindsay , Keating Robert , Patel Nirali , Fonseca Adriana , Donoho Dan , Oluigbo Chima , Myseros John , Narsinh Kazim , Mueller Sabine , Ho Winson , Khatib Ziad , Niazi Toba , Clanton Ryan , Henry Lenora , Potter Wyatt , Marcus Stuart , Benaim Ely , Packer Roger , Syed Hasan 
Published: November 2024

Abstract
Diffuse intrinsic pontine glioma (DIPG) is the leading cause of mortality amongst pediatric neuro-oncologic diseases. Sonodynamic therapy with non-ablative MR-guided focused ultrasound (MRgFUS) is being investigated in multiple clinical trials. We describe safety outcomes and initial efficacy of SDT with 5-ALA for the treatment of pediatric patients with DIPG. Twelve patients with DIPG were treated from August 2022-April 2024 as part of a dose-escalation protocol with SDT in a multicenter Phase 1/2 clinical trial (NCT05123534). MRgFUS was combined with the prodrug SONALA-001 (5-ALA iv) to activate its metabolite, protoporphyrin IX, and thereby induce apoptosis within tumor cells. Treatment is delivered every 4 weeks for up to 12 treatments. Patient ages ranged from 3-23 years and 60% were male. Twelve patients underwent a total of 45 SDT treatments (range 2-9). When enrolled, median tumor volume was 1,337 cm3 (range, 310-2078 cm3) and duration since diagnosis was 5 months. SONALA-001 doses tested were 5 mg/kg and 10 mg/kg. Delivered ultrasonic acoustic energy ranged from 190-444 joules/cm3. After 6 months of median follow-up (range 2-18), 2 partial responses occurred, and 9 of 12 patients had stable or improved baseline symptoms (Lansky Status), including improved mobility and diplopia. One adverse clinical event included a small non-operative epidural hematoma secondary to a stereotactic frame pin. There have been no grade 3 or worse treatment-related adverse events or dose-limiting toxicities. Ten patients are alive a median of 11 months after diagnosis; 2 have deceased; 4 have discontinued treatment. Maximum percent tumor volume changes throughout treatment ranged from a -68% reduction to over 100% enlargement. Preliminary analysis of twelve pediatric patients treated with SDT for DIPG demonstrates acceptable safety outcomes and promising clinical results. Additional patient enrollment and longer follow-up times are required to determine efficacy.
CTNI-75. TRIALS IN PROGRESS: REGISTRY OF SAFETY & EFFICACY IN ADULTS WITH PRIMARY & METASTATIC INTRACRANIAL TUMORS TREATED WITH START (GAMMATILES (CS-131 SOURCE BRACHY-THERAPY)): NCT04427384
Authors: Dunbar Erin , Lee Stuart , Peach Matthew Sean , Wanbo John , Smith Chris , Hansfit Simon , Mertitz Keith , Berkowitz Aviva , Sloan Lindsey , Ferreira Clara , Neil Elizabeth , Kotecha Rupesh , Nowlan Adam , McCracken David , Patel Toral , Wardak Zabi , Richardson Angela , Shah Mitesh , Chowdhary Sajeel , DiNapoli Vincent , Floyd John , Nagib Mahmoud , Wasilewski Andrea , Patel Akash , Rao Ganash , Pham Houng , Ryan Roby , Shen Colette , Robin Adam , Lee Ian , Leng Lewis , Hoang Kim , Olson Jeff , Choutka Ondrej , Mercado Catherine , Chamoun Rouboz , Camarata Paul , Smith William , Babu Harish , Piccioni David , Sevak Parag , Zhu James , Haydon Devon , Aizenberg Michelle , Hoeprich Mark , Williams Brian , Dickinson Lawrence , Baskin David , Farach Andrew , rodriguez alaniz 
Published: November 2024

Abstract

INTRO
This is the first observational registry study of R+STaRT, delivered by Cs-131 sources in permanently implanted resorbable collagen tile carriers, for patients with intracranial tumors.

METHODS
Since October 2020, 37 sites to-date have enrolled 359 patients with primary & metastatic intracranial tumors into the R+STaRT registry to assess the safety & efficacy of the addition of Gamma Tile to medically needed resection. Local control, overall survival, QOL, neurocognition, functional decline, and surgical and radiation associated AE’s are collected at 1, 3, 6, 9,12, 18 and 24 months, then every 6 months through 5 years.

RESULTS
Demographics include 359 patients, avg. age 57 y.o.. 162 malignant gliomas, 125 metastatic tumors, 38 meningiomas, and 34 rare other tumors. 197 Males (163 White, 23 Black, 5 Asian, and other races) and 157 Females (White 121, 28 Black, 0 Asian, and 8 other races). No unexpected outcomes reported in the hands of experienced providers have occurred, although close clinical-radiographic follow-up, to ensure early detection of possible treatment-effects, is paramount. Steroid-use, and above endpoints, continue to be collected.

CONCLUSIONS
In this observational registry of Gamma Tiles (Cs-131 source brachy-therapy) added to medically needed resections for patients with primary and metastatic intracranial tumors continues. Data will be used to benchmark clinical outcomes of R+STaRT therapy and allow for comparisons to existing standard-of-care treatments. The outcome measures captured will allow for evaluation of the potential risks and benefits of this treatment approach for patients in a real-world setting.
CTNI-77. PHASE 1 DOSE FINDING STUDY EVALUATING THE SAFETY, TOLERABILITY, AND EFFICACY OF IOPOFOSINE I 131 IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH INOPERABLE RELAPSED OR REFRACTORY HIGH-GRADE GLIOMAS: A TRIAL-IN-PROGRESS
Authors: Sait Sameer Farouk , Morgenstern Daniel A , Pandit-Taskar Neeta , Das Anirban , Pudel Miriam , Fisher Callie , Zanzonico Pat , Haque Sofia , Longcor Jarrod , Shustov Andrei , Glade-Bender Julia 
Published: November 2024

Abstract
Iopofosine I 131, a radioconjugate therapy targeting tumor lipid rafts, is being assessed in CLOVER-2 [NCT05610891]–an ongoing dose-finding study evaluating iopofosine in children, adolescents, and young adults with relapsed, refractory, recurrent high-grade gliomas (HGGs) and ependymoma. Major inclusion criteria include patients aged 10-25 years, previously confirmed HGGs or ependymoma, ≥1 measurable intracranial lesion (≥10 mm in longest diameter), and performance status ≥60. Patients are assigned 1:1 to 2 treatment arms which will be assessed in parallel. Arm 1 has 2 cycles, each composed of 2 doses of 20 mCi/m2 given 14 days apart (± 1 day). Cycle 2 is given 8 weeks (± 4 days) post-initial infusion. Arm 2 patients receive 3 cycles of 10 mCi/m2 per dose. Patients in either arm are eligible for 1 additional cycle at the physician’s discretion. If after the first 10 patients, Arm 1 is not tolerated, dosing is reduced to 15 mCi/m2 per infusion. If after the first 10 patients in Arm 2 are deemed to be ineffective and Arm 1 is deemed to be tolerated, dosing is increased to 15 mCi/m2 per infusion. Final visits occur 57 days following the last cycle initiation, with quarterly follow-ups in year 1 and annually in years 2 and 3. Primary endpoints include safety, tolerability, and progression-free survival (PFS). Secondary endpoints are dosimetry, recommended phase 2 dosing determination, overall survival, antitumor and therapeutic activity, and duration of response and clinical benefit. Safety analysis uses the Wilson score method and nonparametric Wilcoxon signed-rank test. Efficacy analyses use the Response Assessment in Pediatric Neuro-Oncology criteria and the Kaplan-Meier method to detect a median PFS of 5 months compared to a historical control of 2 months. For 90% power by a 1-sided, 1-sample log-rank test: ≥10 evaluable patients must be enrolled (≤90) across ≤15 sites.
CTNI-79. ASSESSING SYSTEMIC AND LOCAL LEVELS OF LIDOCAINE DURING SURGERY FOR GLIOBLASTOMA
Authors: Riestenberg Robert , Goodarzi Amir , Goodrich Dylan , Chen Shuai , Chen Yichu , Schloemerkemper Nina , Lechpammer Mirna , Bloch Orin , Shahlaie Kiarash 
Published: November 2024

Abstract
The objective of this study is to assess the pharmacokinetics of lidocaine penetration into tumor tissue during glioblastoma surgery. In-vitro studies of glioblastoma have demonstrated co-culture with lidocaine inhibits glioblastoma proliferation via inhibition of TRPM7 channels. TRPM7 is a transmembrane ion channel that modulates proliferation and migration in several human cancers. Scalp block with lidocaine during glioblastoma surgery has been associated with improved survival in human studies. Twelve patients were enrolled in this study. The study group received an intravenous bolus dose of 1.5 mg/kg IBW of lidocaine at induction of anesthesia followed by 2 mg/kg IBW/hr infusion of lidocaine. Craniotomy was performed in the standard fashion. A total of 3 fresh tumor specimens were collected hourly from each patient after confirmation of glioblastoma diagnosis by frozen section. Plasma samples were simultaneously collected for analysis. Lidocaine concentration was measured using mass spectroscopy. The maximum concentration of lidocaine (Cmax), time from bolus to maximum concentration (Tmax), and area under curve from 0-3 hours (AUC) were calculated for each patient. Patients were followed for survival and adverse events. The median tumor specimen Cmax, Tmax, and AUC values were 333 ng/dL (range 226-555), 179 min (range 126-211), and 20665 ng*min/dL (range 8003-55,426), respectively. Peak lidocaine concentration was reached in 6 of 12 cases. Median Cmax and Tmax for plasma samples were 1195 ng/dL (range 951-1475) and 191 min (range 156-211), respectively. Median overall survival was 308 days (range 74-413). Two grade 3 adverse events occurred which were deemed to be unlikely to be related to the study intervention. In conclusion, lidocaine infiltrates tumor tissue when administered intravenously during glioblastoma surgery. Concentrations do not reach levels previously demonstrated to inhibit tumor growth in in vitro studies (roughly 2*108 ng/dL lidocaine). Alternative mechanisms may explain previously observed improved outcomes with lidocaine administration in human studies.