bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-21. PHASE 2 STUDY OF VAL-083 AND RADIOTHERAPY IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM
Authors: Chen Zhong-ping , Guo Cheng-Cheng , Qun-ying Yang , Li Jia-Wei , Wu Shao-xiong , Bacha Jeffrey , Johnson Gregory , Langlands John , Kwan Claire , Kanekal Sarath , Schwartz Richard , Steino Anne , Brown Dennis 
Published: November 2021

Abstract
Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated methylguanine DNA-methyltransferase (MGMT) gene promoter, which confers a limited clinical response to standard-of-care treatment with temozolomide (TMZ), resulting in shorter median survival when compared to patients with a methylated MGMT promoter. VAL-083 is a novel bi-functional DNA targeting agent that induces interstrand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated TMZ resistance in vitro and in vivo. A Phase 2 study has been conducted to evaluate efficacy and safety of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT unmethylated GBM. The study was conducted in 2 stages: Stage 1 was a dose-escalation phase to confirm the dose of VAL-083 in this setting. Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days along with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). At the end of this stage, 30 mg/m2/day of VAL-083 in combination with RT was generally safe and well-tolerated. Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 in combination with RT. All patients have been enrolled, with a total of 29 patients in the study, and 25 patients receiving 30 mg/m2/day VAL-083. All 29 patients have completed treatment and patients are in the follow-up phase of the study. Consistent with our prior experience, myelosuppression was the most common adverse event. As of March 2021, 22/29 (75.9%) subjects had disease progression. The median progression free survival for all patients enrolled was 9.3 (95%CI: 6.4-12.0) months. Sixteen (16/29; 55.2%) patients had died, and median overall survival for all patients enrolled was 19.6 (95%CI: 14.0-22.4) months. Further safety and efficacy updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT03050736.
CTNI-24. A PHASE 1/2 STUDY OF AVAPRITINIB IN PEDIATRIC PATIENTS WITH SOLID TUMORS DEPENDENT ON KIT OR PDGFRA SIGNALING
Authors: Chi Susan , Hsieh Antony , Foley Megan , Shi Hongliang , Swamy Preethi , Rodstrom Jill , Rudoltz Marc 
Published: November 2021

Abstract
Prognosis for pediatric patients with advanced relapsed/refractory (R/R) solid (including central nervous system [CNS]) tumors is poor; response rates are only ~15% with targeted therapies. Germ cell tumors and high-grade glioma (HGG) are the most common with KIT alterations; sarcoma and HGG are the most common tumors with platelet-derived growth factor receptor alpha (PDGFRA) alterations. H3K27M gliomas are dependent on PDGFRA signaling and patients have an overall survival of ~1 year. No KIT/PDGFRA targeted therapies are currently approved for pediatric patients with R/R solid or CNS tumors, or H3K27M gliomas. The selective KIT and PDGFRA inhibitor, avapritinib, demonstrated potent activity against KIT activation-loop (exon 17), juxtamembrane (exon 11), and extracellular-domain (exon 9) mutants (IC50 &lt; 2 nM), and PDGFRA activation-loop (D842V) mutants (IC50 = 0.24 nM); cellular IC50 of PDGFRA wild-type was 95 nM. CNS penetration in preclinical models (brain-to-plasma ratios at steady-state ranging from 0.74–1.00) demonstrated potential for CNS antitumor activity. Avapritinib is approved for the treatment of adults with unresectable/metastatic gastrointestinal stromal tumors (GIST) harboring PDGFRA exon 18 mutations (including D842V) in the USA, and in the EU for adults with unresectable/metastatic GIST harboring a PDGFRA D842V mutation. Objectives of this 2-part phase 1/2, multicenter, open-label study are to assess avapritinib safety, preliminary efficacy, and pharmacokinetics in pediatric patients aged 2 to &lt; 18 years with solid R/R tumors dependent on KIT or PDGFRA signaling, including H3K27M gliomas and no alternative treatment options. Part 1 will enroll ≥ 6 patients; primary endpoint is confirmed age and body surface area physiologically-based pharmacokinetic modeling dose to provide equivalent exposure to the 300 mg adult avapritinib dose. Part 2 will enroll ≥ 25 patients at the recommended avapritinib dose from Part 1; primary endpoint is objective response rate. Avapritinib once-daily will be administered in continuous 28-day cycles.
CTNI-42. PHASE I STUDY OF RUXOLITINIB WITH RADIATION AND TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GRADE III GLIOMAS AND GLIOBLASTOMA
Authors: Rauf Yasmeen , Hufsey Rachel , robinson Kathy , Suh John , Chao Samuel , Murphy Erin , Yu Jennifer , Peereboom David , Ahluwalia Manmeet 
Published: November 2021

Abstract

BACKGROUND
Ruxolitinib is a novel, potent, selective inhibitor of JAK1 (Janus kinase 1) and JAK2 with modest to marked selectivity against TYK2 (tyrosine kinase 2) and JAK3. Ruxolitinib interferes with the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression.

METHODS
Newly diagnosed patients with MGMT not hypermethylated, Glioblastoma or grade III glioma were recruited to Arm 1. Every patient received ruxolitinib and 60 Gy radiation for 6 weeks (2Gy x 30). The dose of Ruxolitinib was administered given the 3 + 3 design. Level 1 or starting dose was 10 mg twice daily, level 2 was 15 mg twice daily, level 3 was 20 mg twice daily. Patients with MGMT hypermethylated glioblastoma or grade III glioma were eligible for Arm 2. Every patient received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks.

RESULTS
45 patients had survival data, 25 patients were in Arm I and 20 arm in II. The median OS and PFS were 18.2 (95% CI: 3.6-NA) months for Arm 1 and were not reached for Arm 2. OS and PFS Rate at 1 year was 61% (95% CI: 43-85%) and 51% (35-76%) for Arm 1, and 95% (85-100%) for Arm 2 (p=0.01 and p= 0.002), respectively. 9 patients had partial response, 16 patients were stable, and 28 patients had progression.

CONCLUSION
Patients that received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks (Arm 2) had significantly better PFS and OS than those that received ruxolitinib + radiation x 60 Gy alone..
CTNI-46. PHASE I OPEN-LABEL, SINGLE-CENTER, DOSE ESCALATION STUDY (NCT02423525) OF PULSATILE AFATINIB IN PATIENTS WITH BRAIN CANCER
Authors: Wagle Naveed , Juarez Tiffany , Carrillo Jose , Heng Annie , Gill Jaya , Nguyen Minhdan , Truong Judy , Boucher Najee , Archer Ashley , Nguyen Hanh , Nomura Natsuko , Yenugonda Venkata , Allnutt Annamarie , Barkhoudarian Garni , Kelly Daniel , Kesari Santosh 
Published: November 2021

Abstract
Afatinib is a small molecule, selective and irreversible ErbB family blocker. In preclinical models it effectively inhibits EGFR, HER2 and HER4 phosphorylation resulting in tumor growth inhibition and is approved for the treatment of EGFR-mutated metastatic non-small cell lung carcinoma and metastatic squamous cell lung carcinoma. Pulse dosing afatinib could potentially increase CNS exposure to reach therapeutic levels while allowing a recovery period to mitigate toxicities. We are reporting the results of a Phase I open-label, single-center, ‘3 + 3’ dose escalation study to determine the safety and tolerability of pulsatile Afatinib in patients with brain cancer and to define a recommended phase 2 dose. The study assessed the exposure of Afatinib in cerebrospinal fluid and serum, objective tumor response according to RANO criteria, progression-free survival, and overall survival, and will explore the association between molecular phenotypes and patient response. In total, 26 patients were screened and 24 were enrolled (median age 60, 78% male, 87.5% Caucasian, glioblastoma N=16, chordoma N=3, brain metastases N=2, meningioma N=1, anaplastic mixed oligoastrocytoma N=1). Patients had received a median of 2.5 prior treatments. The study proceeded through the 4 dosing cohorts without reaching dose-limiting toxicity: Cohort 1 (80mg every 4 days) N=3; Cohort 2 (120mg every 4 days) N=3; Cohort 3 (180mg every 4 days) N=7, including replacement patients; Cohort 4 (280mg every 7 days) N=11. Diarrhea (75%), rash (75%), nausea/vomiting (37.5%), fatigue (29.2%), anorexia (25%), and limb edema (16.7%) were the most common side effects. There were no CTCAE defined grade 4 toxicities. Grade 3 side effects infrequently occurred in the highest dosing cohort and once in each cohort 2 and 3. These results demonstrate that pulsatile Afatinib at a dose of 280mg every 7 days is safe and tolerable for patients with brain involving cancers.
CTNI-52. RETROSPECTIVE ANALYSIS OF USING RADIOTHERAPY WITH CONCURRENT TEMOZOLOMIDE AND TUMOR TREATING FIELDS FOR CHINESE PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Wang Yang , Wu Jingsong , Qin Zhiyong , Wang Enmin , Yao Yu , Zhuang Dongxiao , Liang Lipin , Ni chunxia , Lu peijiang , Chen Shu , Li Chao 
Published: November 2021

Abstract

OBJECTIVES
Tumor Treating Fields (TTFields) has been shown to improve the overall survival of newly diagnosed GBM (ndGBM) when combined with Temozolomide (TMZ) in the EF-14 trial. Preclinical studies suggested synergistic effects between TTFields and radiotherapy. This study is aimed to examine the safety and efficacy of combination therapy (chemoradiation concurrent with TTFields treatment) for ndGBM patients in China.

METHODS
From July 2020 to May 2021, 33 ndGBM patients were treated with combination therapy (radiation target volume following NCCN guidelines). Eight patients had transducer array removed during radiotherapy, others retained transducer array on scalp. All patients had assessment every two months by MRI scan. The adverse reactions and monthly compliance data for TTFields treatment were recorded.

RESULTS
Twenty-five patients have completed the combination therapy. Three patients retained transducer array during radiotherapy but did not limit the scalp dose (mean: 21.7Gy). As a result, Grade 2 cutaneous adverse reactions developed, and TTFields treatment was suspended. Four patients suspended TTFields treatment due to other adverse reactions. The remaining patients who had limited scalp doses (mean &lt; 20Gy) had no suspension or delay in combination therapy due to cutaneous adverse reactions. The median time of TTFields treatment during radiotherapy is 21.24 hours/day (IQR:19.26,22.08). Two patients had progressive disease, 1 died of pulmonary infection, and 30 had stable disease. The incidence of cutaneous AE was 48.5% (16/33), Grade1: 27.2% (9/33), Grade 2: 21.2% (7/33), and Grade 3: 3% (1/33).

CONCLUSIONS
The combination therapy was well tolerated in Chinese patients with ndGBM. Removing transducer array during radiotherapy may increase the frequency of array replacement while reducing the patient's daily treatment time. However, retaining transducer array will increase cutaneous adverse reactions. Scalp dose limitation is required yet it allows a maximum duration of TTFields. Further follow-ups are ongoing.
DDRE-05. LONG-TERM OUTCOME OF INTRATHECAL CHEMOTHERAPY WITH PEMETREXED IN LEPTOMENINGEAL METASTASIS FROM NON-SMALL CELL LUNG CANCER WITH EGFR-MUTATION: A CASE REPORT
Authors: Wang hui , Zhou Jiangfen , Wen Lei , Hong Weiping , Cai Linbo 
Published: November 2021

Abstract
Leptomeningeal metastasis (LM) is fatal complication of non-small cell lung cancer (NSCLC) ,which has a poor prognosis and lacks effective treatments. Pemetrexed, a multitargeted antifolate agent, has demonstrated antitumor activity, a few studies have shown intrathecal pemetrexed (IP) controllable toxicities and potential promising efficacy for LM from NSCLC patients. We report a patient who diagnosed with LM from NSCLC harboring epidermal growth factor receptor (EGFR) mutation in exons 21 via typical neurological symptoms, magnetic resonance imaging (MRI) and positive cerebrospinal fluid (CSF) cytology. The curative effect of tyrosine kinase inhibitor (TKI) targeted drugs was maintained for a short time, the first-generation TKI icotinib was 4 months, and the third-generation osimertinib was 4 months. Then the patient received IP, and osimertinib continued. 30 mg of pemetrexed were implemented on day 1 every weeks for 8 weeks via lumbar puncture, then 50 mg of pemetrexed on day 1 every 4 week for 8 times. This treatment regimen resulted in the alleviation of the neurological symptoms, the CSF level of carcinoembryonic antigen also decresed without obvious side effects. At the time of this manuscript’s submission, she had maintained stable disease (SD) for more than 11 months. To our knowledge, this study provides the first clinical evidence that longterm intrathecal chemotherapy with pemetrexed providing a therapeutic approach against LM from NSCLC.
DDRE-10. SCREENING OF EPIGENETIC COMPOUNDS IN GLIOMA AND GLIOBLASTOMA IDENTIFIES NOVEL THERAPEUTICS FOR THEIR POTENTIAL TREATMENT
Authors: Tatman Philip , Wroblewski Tadeusz , Fringuello Anthony , Scherer Sam , Foreman William , Damek Denise , Youssef Samy , Lillehei Kevin , Ormond David , Graner Michael 
Published: November 2021

Abstract

BACKGROUND
28% of primary central nervous system tumors are glioma and glioblastoma. These tumors are responsible for 80% of malignant brain neoplasms and most brain tumor related deaths. Despite modern therapies, patients with grade II gliomas have an average survival of 8-15 years, while patients with grade III tumors have an average survival of 3-5 years, and patients with glioblastoma have an average survival of 12-15 months. The lack of a curative treatment for this group of tumors supports additional research and novel approaches to identify more effective therapies.

METHODS
In this study, we developed a high-throughput drug screen and culture system to identify epigenetic inhibitor compounds with the potential to reduce glioma and glioblastoma viability.

RESULTS
We screened 33 tumors: 18 glioblastoma, 8 oligodendroglioma, and 7 astrocytoma. The top three most effective compounds across the full glioma cohort were all HDAC inhibitors; in order from most effective: panobinostat (average tumor viability = 52.5% +/-14.1SD; p=2.16x10-61), LAQ824 (average tumor viability = 58.1% +/-18SD; p=1.48x10-45), and HC Toxin (average tumor viability = 64% +/-21.1SD; p= 1.16x10-33). Additionally, HDAC inhibition was also the most effective across each histopathological glioma type: astrocytoma, oligodendroglioma, and glioblastoma. UNC0631(G9a inhibitor) and JIB-04(KDM inhibitor) were the most effective compounds in the six recurrent tumors, though HDAC inhibition was still significantly effective in this group. We also evaluated drug sensitivity with respect to tumor grade, prior treatment, de novo vs progressive etiology, EGFR amplification, IDH mutation, MGMT methylation, and patient gender.

CONCLUSIONS
After screening a large glioma cohort against a panel of epigenetic inhibitors, we found HDAC inhibition most effectively reduced tumor viability across all histopathological types and grades. These findings require further in vivo validation.
DDRE-14. OPTIMIZING MDM2 INHIBITION FOR THE TREATMENT OF HIGH-GRADE GLIOMA
Authors: Rendo Veronica , Lupien Leslie , Khuu Nicholas , Pelton Kristine , Elcavage Lara , Lu Sophie , Khadka Prasidda , Langhnoja Jaldeep , Phoenix Tim , Ligon Keith , Bandopadhayay Pratiti , Beroukhim Rameen 
Published: November 2021

Abstract
A majority of high grade gliomas retain a wild-type TP53 gene and are amenable to strategies for activation of the pathway to inhibit tumor growth. The interaction between p53 and MDM2 has served as target for such strategies currently in clinical trials for glioblastoma. As the effects and resistance mechanisms of MDM2 inhibition (MDM2i) remain poorly understood in glioma, we performed genomic and transcriptomic analyses in patient-derived models to better characterize sensitive tumors and identify putative biomarkers of drug response. Treatment with an MDM2 inhibitor (KRT232/AMG232) impaired the growth of cell lines with wild-type TP53 status, particularly in tumors with amplification of MDM2/4 or PPM1D activating mutations. Treatment with KRT232 upregulated both cell cycle arrest and apoptotic cellular responses, with unique temporal and transcriptional differences correlated with MDM2/4 or PPM1D status. In other tumors resistance to MDM2i is mainly mediated by TP53 mutations, but in a subset of chronic KRT232-treated glioma models we noted lack of TP53 mutations and identified cell state and transcriptional changes as potentially more treatable mediators of resistance.
DDRE-21. LOMUSTINE AND TARGETED-CYTOKINE THERAPY: A BENEFICIAL LIAISON FOR RECURRENT GLIOBLASTOMA
Authors: Weiss Tobias , Look Thomas , Puca Emanuele , De Luca Roberto , Hemmerle Teresa , Roth Patrick , Neri Dario , Weller Michael 
Published: November 2021

Abstract
Treatment options for recurrent glioblastoma are limited and except from regorafenib (potentially), no other agent has demonstrated superior activity to lomustine. Therefore, there is an urgent need for more effective treatment strategies for recurrent glioblastoma.
We investigated the combination of lomustine or bevacizumab that are frequently used for recurrent glioblastoma with L19TNF (onfekafusp alfa), a systemically administered tumor-stroma targeting antibody-cytokine fusion protein that enables a targeted delivery of tumor-necrosis factor (TNF)a to the tumor. In immunocompetent orthotopic glioma mouse models, the combination of lomustine and L19TNF demonstrated the strongest anti-tumor activity, acted in synergy and cured a majority of tumor-bearing mice, whereas lomustine or L19TNF monotherapy only had only very limited anti-tumor activity. Ex vivo profiling of the tumors and tumor-infiltrating immune cells from immunocompetent or immunodeficient hosts demonstrated immune-dependent cytotoxic and cytostatic effects on the glioma cells, and a strong increase of tumor-infiltrating immune cells upon combination therapy in immunocompetent models. Based on these encouraging results, we translate this combinatorial therapy to patients with recurrent glioblastoma. For the first patients, the treatment with lomustine and L19TNF was well tolerated and led to stable disease with a reduction in tumor perfusion. More patients are recruited in an ongoing phase I/II clinical trial with lomustine and L19TNF for patients with recurrent glioblastoma (NCT04573192).
DDRE-22. DISRUPTING REDOX BALANCE VIA THE TETRAHYDROBIOPTERIN PATHWAY IN GLIOBLASTOMA
Authors: Tuy Kaysaw , GC Sajina , Chen Wei , Harrison David , Aleman John , Hjelmeland Anita 
Published: November 2021

Abstract
Aberrant redox statuses are observed in glioblastoma (GBM), and we previously identified GTP cyclohydrolase I (GCH1) to be a redox regulator upregulated in brain tumor initiating cells (BTICs). GCH1 is a rate-limiting enzyme in the de novo synthesis of tetrahydrobiopterin (BH4), a cofactor that produces catecholamine precursors and nitric oxide (NO) and, once used, becomes 7,8-dihydrobiopterin (BH2). Regeneration of BH2 into BH4 by dihydrofolate reductase (DHFR) helps to maintain proper BH4/BH2 ratios for redox balance. Although the BH4 pathway has traditionally been studied in the vasculature system for its regulation of NO, our previous work and that of others suggests the GCH1/BH4 pathway plays a critical redox role including in neoplastic cells. In silico analysis of primary and recurrent gliomas indicate high expression of BH4 related enzymes that correlated with worse patient survival in both primary and recurrent gliomas. The observed elevation of the BH4 pathway not only emphasizes its importance, but a therapeutic opportunity for improving survival in glioma patients. By repurposing FDA approved drugs known to cross the blood brain barrier and previously suggested as anti-glioma therapies, combining inhibitors for the de novo synthesis (sulfasalazine) and regeneration (pyrimethamine) of BH4 could prove to be an effective strategy for targeting the GCH1/BH4 through redox disruption. Preliminary data BTICs isolated from patient derived xenografts (PDXs) indicated reduced viability when treated with sulfasalazine (SASP) and pyrimethamine (PYR). Furthermore, we observed lower/depleted levels of BH4 relative to BH2 when BTICs were treated with SASP and PYR. Lastly, there is an increase in mitochondrial ROS upon SASP and PYR treatment, suggesting dysregulated redox states. Importantly, temozolomide resistant GBM cells remained sensitive to SASP and PYR. Taken together, our preliminary data suggests the plausibility of targeting the GCH1/BH4 pathway with SASP and PYR to disrupt redox balance in glioma through the depletion of BH4.
DDRE-31. MITOCHONDRIAL TRAFFICKING AS A TARGET FOR GBM THERAPY
Authors: Lepe Javier , Douglas Christopher , Lomeli Naomi , Di Kaijun , Das Bhaskar , Bota Daniela 
Published: November 2021

Abstract
Glioblastoma (WHO Grade IV glioma) is the most aggressive brain cancer. The current standard of care treatment includes surgery, radiation, and chemotherapy. Tumor recurrence is almost inevitable as less than 50% of patients survive more than two years. The low survival rate poses a dire need to develop an effective therapy for GBM patients. GBM cells are resistant to treatment, as they activate their DNA damage response mechanisms to overcome the effects of radiation and temozolomide (TMZ) treatments. Recurrent tumors can arise from slow cycling and self-renewing stem/tumor-initiating cells resistant to radiation and TMZ. No second-line therapy was proven to prolong survival after TMZ failure. Magmas (Mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) is a subunit of the TIM23 complex regulating precursor protein trafficking into the mitochondrial matrix. Magmas is encoded by pam16, known to be upregulated in human pituitary adenomas, prostate cancer and GBM. Previous studies have demonstrated that Magmas negatively regulates the stimulatory activity of Pam18, which in turn stimulates the ATPase activity of mitochondrial heat shock protein 70 (mtHsp70). No small molecules targeting Magmas are in clinical use. We developed a novel small molecule inhibitor (BT9) that has been specifically designed to inhibit Magmas binding to Pam18. BT9 induces apoptosis through cleavage of caspase-3, reduced mitochondrial respiration and glycolysis. Our recent findings also demonstrate that BT9 treatment reduced protein trafficking of Lon protease into the mitochondrial matrix. Pretreatment of glioma cells with BT9 sensitizes cells to radiation treatment and enhances the TMZ activity. BT9 can cross the blood-brain-barrier and improve survival in intracranial glioma PDX models. BT9 has potential therapeutic value by directly dysregulating mitochondrial function in GBM, enhancing radiation and chemotherapy response, and improving survival in a relevant animal model.