bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-65. COMBINED RITUXIMAB, METHOTREXATE, PROCARBAZINE, VINCRISTINE, AND CYTARABINE (R-MPV-A) TREATMENT FOR PATIENTS WITH RELAPSED PRIMARY CNS LYMPHOMA
Authors: Nagane Motoo , Sasaki Nobuyoshi , Kobayashi Keiichi , Saito Kuniaki , Shimada Daisuke , Matsumoto Yoshie , Iijima Shohei , Yamagishi Yuki , Shimizu Saki , Takayama Nobuyuki , Shiokawa Yoshiaki 
Published: December 2020

Abstract

BACKGROUNDS
Standard of care for patients with primary CNS lymphoma (PCNSL) has been high-dose methotrexate (HD-MTX)-based multiagent immunochemotherapy including an induction R-MPV with consolidation whole-brain radiotherapy (WBRT) and HD-cytarabine to achieve complete remission, however, the optimal treatment for relapsed/refractory (r/r) PCNSL has not been established yet, besides the recent approval of a BTK inhibitor, tirabrutinib, in Japan. We evaluated retrospectively efficacy of R-MPV-A for r/rPCNSL.

PATIENTS
Histologically proven PCNSL patients treated at relapse in our institution from April 2000 to November 2019 were analyzed. Outcomes were compared between those treated with RMPVA or other regimens.

RESULTS
Among 148 PCNSL patients identified, 73 had at least one relapse, of whom 47 received salvage chemotherapy including 23 treated with RMPVA either at the first relapse (11) or at the second or later relapse (12). Median age/KPS of this salvage RMPVA group were 71 (42–87)/80 (40–100). Nine patients were pretreated with the first-line RMPVA. HD-cytarabine was given to 13 patients. Median number of RMPV cycles was 8 (1–4 cycles: 10; 8 cycles 13). CR/CRu were achieved in 19 (83%), response rate was 87%, while there were two PDs (9%). After median follow-up of 21.9 months, the median PFS after salvage RMPVA was 13.0 m (95%CI: 9.1–16.9), 1-year overall survival (OS) was 82%, median OS was 70.0 m (95%CI: 12.9–127.1), which were longer than those in 24 patients with salvage treatment other than RMPVA (mPFS 4.4 m, P=0.054; mOS 13.6 m, P=0.009). Among patients with salvage RMPVA, HD-cytarabine was associated with better PFS (P=0.066), and complete responses were significantly correlated with longer OS. Treatment was generally well-tolerated but there was one treatment-related death.

CONCLUSIONS
Salvage RMPVA at relapses was active and associated with longer survival compared with other regimens, necessitating further development of salvage regimens incorporating tirabrutinib in the future studies.
CTNI-68. EFFICACY OF TTFIELDS IN ELDERLY PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM) – SUB-GROUP ANALYSIS OF THE EF-14 TRIAL
Authors: Ram Zvi , Kim Chae-Yong , Zhu Jay-Jiguang 
Published: December 2020

Abstract

BACKGROUND
Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment that utilizes low intensity alternating electric fields delivered non-invasively to the tumor using a portable medical device. In the EF-14 phase 3 study leading to FDA approval, TTFields significantly extended survival in newly diagnosed GBM when added to maintenance temozolomide (TMZ). Elderly GBM patients usually have worse prognosis and often receive only partial treatment for the disease. This sub-group analysis examined the effects of TTFields in the elderly population (≥65 years of age) enrolled in the EF-14 study.

METHODS
All 134 elderly patients (≥65 years of age) from the EF-14’s intent-to-treat population were included in the analysis, Overall survival (OS) and progression-free survival (PFS), as well as adverse event frequency and severity were compared between the TMZ/TTFields arm and the TMZ alone arm.

RESULTS
The median age was 69 (range: 65–83), median KPS was 90%, and 69% were male. Median PFS from randomization was 6.5 months versus 3.9 months in the TMZ/TTFields versus TMZ alone arms, respectively (hazard ratio [HR], 0.47 [95%CI 0.30, 0.74] P&lt; 0.0236). Median OS was 17.4 months versus 13.7 months in the TMZ/TTFields versus TMZ alone arm, respectively (HR 0.51 [CI 0.33, 0.77] P&lt; 0.020). Serious adverse events (SAEs) were reported in 39% of patients treated with TMZ/TTFields and in 33% of patients treated with TMZ alone. None of the SAEs were considered related to TTFields but attributed to TMZ or to the underlying disease. Grades 1–2 skin AEs related to TTFields were observed in 51% of patients.

CONCLUSION
Consistent with the overall outcome of the EF-14 study, elderly patients treated with TMZ/TTFields showed significantly better OS compared to patients on TMZ alone, and without increase in grade III or IV toxicity.
CTNI-69. PRECISION NEURO-ONCOLOGY TREATMENT GUIDED BY NEXT GENERATION SEQUENCING (NGS)-BASED COMPREHENSIVE GENOMIC PROFILING: REAL WORLD EXPERIENCE IN HONG KONG
Authors: Lam Tai-Chung , Chen Shu Jen , Tan Kien Thiam , Li Lai Fung , Pu Jenny K S 
Published: December 2020

Abstract

BACKGROUND
The development of next generation sequencing (NGS) based comprehensive genomic profiling (CGP) has enabled identification of druggable somatic mutations in brain tumours. This cohort reviewed the efficacy of CGP-guided precision treatment in a tertiary neuro-oncology centre.

METHODOLOGY
From May 2017 to May 2020, CGP were arranged for 43 patients. All patients had exhausted conventional treatments or received CGP for clinical trial screening. Targeted deep NGS was used to assess the mutational status, single nucleotide variant, small insertions and deletions and copy number variant of 440 cancer-related genes.

RESULTS
The diagnoses of the 43 patients were GBM (n=23), high grade glioma (n=11), brain metastases (n=4), chordoma (n=3), atypical choroid plexus papilloma (n=1) and meningioma (n=1). In most of the patients (42/43, 97.7%), CGP identified at least one druggable targets with a median of 3. Based on the CGP, 27 patients received precision treatment (62.7%). Among these, 14 were GBM and 6 were other high grade glioma. Treatment given included PARP inhibitors, immunotherapy, multi-kinase inhibitor, selective CDK4/6 inhibitor and mTOR inhibitor. Clinical benefit was achieved in 20 patients out of 27 (74%), including 2 complete response (7.4%), 9 partial response (33.3%) and 9 stable disease (33.3%). The median progression free survival (PFS) were 183 days [95% confident intervals (CI): 81–302 days]. For GBM/high grade glioma patients, median PFS was 125 days [95% CI: 52–215] and six-month PFS was 32.7%. Treatment toxicity was mild except two patients developed grade 3 complications and one grade 5 complication (fatal neutropenic fever). For the 16 patients who did not receive precision treatment, one had no druggable target identified, nine were still stable on standard therapies, 6 were too weak when CGP was available.

CONCLUSION
CGP guided precision treatment for selected, advanced neuro-oncological patients yielded modest clinical efficacy and satisfactory safety profile in real world setting.
CTNI-74. PHASE 3 TRIDENT TRIAL: CONCOMITANT RADIATION THERAPY (RT) AND TEMOZOLOMIDE +/- TUMOR TREATING FIELDS (TTFIELDS) IN NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Shi Wenyin , Kleinberg Lawrence , Jeyapalan Suriya A , Goldlust Samuel , Nagpal Seema , Combs Stephanie E , Roberge David , Nishigawa Ryo , Grossman Rachel , Glas Martin 
Published: December 2020

Abstract

BACKGROUND
Tumor treating fields (TTFields) is a non-invasive, regional antimitotic treatment approved as a standard-of-care for newly diagnosed glioblastoma (ndGBM). In the EF-14 Phase 3 trial, TTFields (200 kHz) plus temozolomide (TMZ) significantly increased survival of ndGBM patients without increasing systemic toxicity. TTFields-related AEs were mainly skin AEs. In preclinical models, TTFields increase the therapeutic effects of radiation therapy (RT). A pilot study showed that TTFields concomitant with RT and TMZ is well tolerated. The benefit of concomitant TTFields with RT and TMZ will be tested in the TRIDENT trial.

METHODS
TRIDENT is an international phase III randomized trial comparing standard RT with TMZ vs the triple combination of RT/TMZ with concomitant TTFields. RT is delivered through the TTFields arrays. Patients in both arms will receive maintenance TTFields/TMZ. TTFields (200 KHz) will be delivered &gt;18 hours/day using Optune. Patients will continue TTFields treatment until second recurrence. Patients with pathologically confirmed ndGBM, ≥ 18 years, KPS ≥ 70, either sex, post-surgery or biopsy, and amenable for RT/TMZ therapy will be stratified by extent of resection and MGMT promoter methylation status. The primary endpoint is overall survival (OS). Secondary end points: progression free survival (PFS; RANO), 1- and 2-year survival rates, overall radiological response (ORR; RANO), progression-free survival (PFS6M, PF12M, PFS2Y); severity and frequency of AEs (CTCAE V5.0); pathological changes in resected GBM tumors post treatment; quality of life (EORTC QLQ-C30); and correlation of OS to TTFields compliance. The hypothesis is that concomitant TTFields/RT/TMZ will significantly improve OS versus RT/TMZ. Sample size (N=950; 475/arm) will detect a HR&lt; 0.8 with 5% type I error. Survival will be measured from the time of randomization until date of death. At the time of analysis, patients lost to follow-up or still on protocol follow-up will be censored at the last date known to be alive.
CTNI-75. A PILOT CLINICAL TRIAL OF OROTECAN (VAL-413), A NOVEL ORAL DOSAGE FORMULATION OF IRINOTECAN: IMPLICATIONS FOR PEDIATRIC BRAIN TUMORS
Authors: Brown Dennis , Bacha Jeffrey , Wagner Lars , Leggas Markos , Kanekal Sarath , Lopez Lorena , Sankar Neil 
Published: December 2020

Abstract
Tumors of the brain and of the central nervous system (CNS) are the most common solid tumors in children. Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also used off-label in a wide range of treatment regimens for recurrent adult and pediatric tumors including glioblastoma, pediatric glioma and medulloblastoma. Recently, commercially available IRN-IV has been administered orally (IRN-IVPO) in pediatric patients to reduce intravenous administration-related side effects, improve convenience and reduce clinic time and costs. Unfortunately, the poor palatability of this preparation leads to poor compliance, especially in pediatric patients. VAL-413 is novel formulation developed to improve tolerability of oral irinotecan. The current study (NCT04337177) evaluates the safety and pharmacokinetics of VAL-413 administered with temozolomide for treatment of recurrent pediatric solid tumors. METHODS: Up to 20 patients ≥ 1 to ≤ 30 years of age with recurrent pediatric solid tumors will be enrolled. The primary objective is to establish the recommended phase II dose of VAL-413 when given in combination with temozolomide. Secondary objectives include characterization of the pharmacokinetics of VAL-413 vs. IRN-IVPO, evaluating palatability of VAL-413, assessing the toxicity profile of VAL-413 in combination with temozolomide, and assessment of tumor response. Toxicity is evaluated based on CTCAEv5 and tumor response based on RECISTv1.1. An update on the progress of this trial will be presented.
CTNI-76. PHASE 2 CLINICAL TRIAL OF VAL-083 IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM
Authors: Chen Zhong-ping , Guo Cheng-Cheng , Yang Qun-ying , Wu Shao-xiong , Li Jia-Wei , Bacha Jeffrey , Johnson Greg , Langlands John , Schwartz Richard , Kwan Claire , Kanekal Sarath , Steino Anne , Lopez Lorena , Brown Dennis 
Published: December 2020

Abstract
Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated methylguanine DNA-methyltransferase (MGMT) promoter region, which confers a limited response to standard-of-care treatment with temozolomide (TMZ), resulting in shorter median survival when compared to patients with methylated MGMT promoter. VAL-083 is a novel bi-functional DNA targeting agent that induces inter-strand 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 initiated for VAL-083 in newly diagnosed MGMT unmethylated GBM. The study has 2 stages: Stage 1 is a dose-escalation safety and tolerability phase to confirm the phase 2 dose of VAL-083 when administered concurrently with radiation therapy (RT). 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). The dose escalation stage is complete, and 30 mg/m2/day of VAL-083 in combination with RT was generally safe and well-tolerated. Stage 2 comprises an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 in combination with RT. As of June 2, 2020, all patients have been enrolled, with a total of 29 patients in the study, and 25 patients receiving 30 mg/m2/day VAL-083. Of the 29 patients enrolled, 27 have completed their prospectively planned MRI scans and had their initial assessment for tumor response. Two additional patients died prior to their post-cycle 3 MRI. Consistent with our prior experience, myelosuppression was the most common adverse event. Three patients have experienced dose-limiting toxicities - one (1/3; 33%) at the 40 mg/m2/day and two (2/25; 8%) at the 30 mg/m2/day dose. Further safety and efficacy updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT03050736.
CTNI-77. EF-19, A POST-APPROVAL REGISTRY STUDY OF TUMOR TREATING FIELDS (TTFIELDS) IN RECURRENT GLIOBLASTOMA (rGBM)
Authors: Zhu Jay-Jiguang , O’Donnell Robert T , Goldlust Samuel , Ram Zvi 
Published: December 2020

Abstract

BACKGROUND
Tumor Treating Fields (TTFields) are an anti-mitotic therapy of alternating electric fields delivered non-invasively to the tumor. In phase 3 studies leading to FDA-approvals, TTFields plus temozolomide (TMZ) significantly extended survival in newly diagnosed GBM, and achieved comparable survival to best standard of care (BSC) as monotherapy in recurrent GBM (rGBM). The EF-19 study evaluated efficacy of TTFields vs BSC in rGBM in post-approval real-life setting.

METHODS
This registry trial (192 rGBM patients, &gt;21 yrs, KPS &gt; 70) were treated with TTFields (200 kHz, &gt;18h/day). Primary endpoint was overall survival (OS); secondary endpoints were OS in the per protocol (PP) population, time to treatment failure and adverse events (AEs). The registry data were compared to OS of all 117 patients in EF-11 BSC group (Stupp EJC 2012). The sample size (N=192) was based on non-inferiority log-rank test with two-sided alpha (0.05), 80% power, HR of 1.0 comparing TTFields to control with an upper one-sided 95% CI of HR &lt; 1.375.

RESULTS
Median OS with TTFields versus EF-11 BSC was 7.4 versus 6.4 months, p=0.053; HR = 0.64 (95%CI 0.46–0.91, Cox-test P=0.012). Median OS (PP) with TTFields versus EF-11 BSC was 8.1 months versus 6.5 months; p=0.045; HR 0.65. OS was significantly higher TTFields as the 95% CI upper limit of HR was lower than the pre-defined threshold of 1.375. The overall incidence of AEs was lower with TTFields than EF-11 BSC (67% vs. 95%). The median time to treatment failure was longer in the TTFields arm (3.3 months (95% CI 2.6, 3.9) versus BSC arm (1.6 months; 95% CI 1.1, 1.9); HR=0.53 (95% CI 0.41, 0.68, p&lt; 0.0001). Skin AE was the most common AE in the TTFields arm.

CONCLUSION
The results of the EF-19 registry study confirm the effectiveness and safety of TTFields monotherapy in rGBM.
CTNI-78. A PEDIATRIC AND YOUNG ADULT PHASE I DOSE ESCALATION SAFETY STUDY OF BXQ-350 FOR REFRACTORY SOLID AND CENTRAL NERVOUS SYSTEM TUMORS
Authors: Setty Bhuvana , AbdelBaki Mohamed , DeWire Mariko , Cripe Timothy , Curry Rich 
Published: December 2020

Abstract

BACKGROUND
BXQ-350 is a novel agent composed of the multifunctional, lysosomal activator protein Saposin C (SapC) and dioleoyl- phosphatidylserine (DOPS) and has demonstrated antitumor effects in both in vitro and in vivo preclinical models. Many tumors, including high-grade glioma and diffuse intrinsic pontine glioma (DIPG), and cells of tumor vasculature have aberrantly-exposed phosphatidylserine (PS)-rich domains on the cell surface. BXQ-350 is an anti-tumor agent in development from Bexion Pharmaceuticals, Inc. that selectively targets tumor cell PS, particularly those translocated to the outer leaflet of the plasma membrane in tumor cells. BXQ-350 activates and participates in various cellular processes, including apoptosis and necrosis, and may also exhibit novel mechanisms leading to cell death that require further investigation.

METHODS
Nine refractory solid (2) and central nervous system (7) tumor patients (5F:4M, age 4–23 years of age) were enrolled in a 2-site dose escalation Phase I first-in-pediatric trial (NCT03967093) which completed in 2019. All patients received at least one dose of BXQ-350 which was administered as an intravenous infusion. Dosing began at 1.8 mg/kg and escalated to the highest planned dose level of 3.2mg/kg.

RESULTS
There were no BXQ-350-related serious adverse events, dose limiting toxicities or withdrawals. The highest planned dose of 3.2 mg/kg was achieved safely but a maximum tolerated dose was not established. One osteosarcoma patient had progressive disease prior to completing cycle one of treatment and was removed from trial. Eight patients (DIPG-3, HGG-1, GBM-1, Pineoblasotoma-1, Ependymoma-1, Osteosarcoma-1) completed at least one cycle, with one DIPG patient completing cycle five.

CONCLUSION
BXQ-350 was well tolerated with no significant dose-limiting toxicities at the highest planed dose level. A pediatric Phase I trial in newly diagnosed patients is planned for 3rd quarter 2020.
CTNI-79. PRICOTTF TRIAL: A PHASE I/II TRIAL OF TTFIELDS PRIOR AND CONCOMITANT TO RADIOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Kebir Sied , Lazaridis Lazaros , Schmidt Teresa , Oster Christoph , Pierscianek Daniela , Guberina Nika , Kleinschnitz Christoph , Proescholdt Martin , Hau Peter , Grosu Anca-Ligia , Sure Ulrich , Scheffler Björn , Stuschke Martin , Glas Martin 
Published: December 2020

Abstract

OBJECTIVE
Survival rates were significantly improved when adding TTFields to adjuvant chemotherapy with temozolomide in patients with newly diagnosed glioblastoma (nGBM) in the phase 3 EF-14 trial. TTFields therapy is applied at 200 kHz by arrays that are placed at the patients’ scalp. In preclinical studies, the combination of TTFields and radiotherapy demonstrated synergistically enhanced efficacy in GBM cells. Here, we present the PriCoTTF trial, which is currently enrolling nGBM patients and will assess the safety and efficacy of TTFields initiated prior and concomitant to radiochemotherapy.

METHODS
After surgery and complete wound-healing, TTFields therapy will be initiated in newly diagnosed GBM patients. TTFields therapy will continue throughout radiochemotherapy and adjuvant chemotherapy for a total of approximately 9 months. Radiotherapy will be conducted through the arrays, by which TTFields therapy is delivered. Totally, thirty-three patients will be enrolled in two arms. In arm A, 20 adult patients will be enrolled to receive normo-fractionated radiotherapy and in arm B, 13 elderly patients will be treated by hypo-fractionated radiotherapy. The patients will receive chemotherapy according to institutional standard and interdisciplinary tumor conference.

RESULTS
Safety and tolerance based on the frequency of pre-specified treatment-limiting toxicities is defined as primary endpoint of the trial. Secondary endpoints include the frequency of adverse events, progression-free survival (PFS), and overall survival (OS). The trial is currently enrolling patients at four sites in Germany. To date, 13 patients were included (May 2020). Initial practical experiences will be presented.

CONCLUSION
The combination of TTFields and radiotherapy is an encouraging approach to further improve survival of GBM patients. In the presented phase I/II trial, the safety and efficacy of TTFields initiated prior and concomitant to RT in newly diagnosed GBM will be assessed. In addition, initial efficacy data (phase II) can serve as a rationale for a randomized phase III trial.
DDRE-07. DIPG HARBOUR ALTERATIONS TARGETABLE BY MEK INHIBITORS, WITH ACQUIRED RESISTANCE MECHANISMS OVERCOME BY COMBINATORIAL INHIBITION
Authors: Izquierdo Elisa , Carvalho Diana , Mackay Alan , Temelso Sara , Boult Jessica K R , Molinari Valeria , Stubbs Mark , Grabovska Yura , Yu Lu , Choudhary Jyoti , Depani Sarita , o’Hare Patricia , Robinson Simon P , Hubank Michael , Hargrave Darren , Jones Chris 
Published: December 2020

Abstract
The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In the era of precision medicine, targeted therapies represent an exciting treatment opportunity, yet resistance can rapidly emerge, playing an important role in treatment failure. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling (methylation BeadArray, exome, RNAseq, phospho-proteomics) linked to drug screening in newly-established patient-derived models of DIPG in vitro and in vivo. We identified a high degree of in vitro sensitivity to the MEK inhibitor trametinib (GI50 16-50nM) in samples, which harboured genetic alterations targeting the MAPK pathway, including the non-canonical BRAF_G469V mutation, and those affecting PIK3R1 and NF1. However, treatment of PDX models and of a patient with trametinib at relapse failed to elicit a significant response. We generated trametinib-resistant clones (62-188-fold, GI50 2.4–5.2µM) in the BRAF_G469V model through continuous drug exposure, and identified acquired mutations in MEK1/2 (MEK1_K57N, MEK1_I141S and MEK2_I115N) with sustained pathway up-regulation. These cells showed the hallmarks of mesenchymal transition, and expression signatures overlapping with inherently trametinib-insensitive primary patient-derived cells that predicted an observed sensitivity to dasatinib. Combinations of trametinib with dasatinib and the downstream ERK inhibitor ulixertinib showed highly synergistic effects in vitro. These data highlight the MAPK pathway as a therapeutic target in DIPG, and show the importance of parallel resistance modelling and rational combinatorial treatments likely to be required for meaningful clinical translation.