bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTIM-27. PHASE I/II STUDY OF CONTROLLED IL-12 AS IMMUNOTHERAPY FOR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Goldman Stewart , Mueller Sabine , Chi Susan , Saratsis Amanda , Allen Rudy , Buck Jill , Demars Nathan , Hadar Nira , Estupinan Taylor , Miao John , Walsh Erin , Gelb Arnold , Cooper Laurence 
Published: December 2020

Abstract
DIPG, which is the leading cause of pediatric brain cancer death with no effective treatment, has neither a highly immunosuppressive nor inflammatory tumor microenvironment (TME). Therefore, eliciting a pro-inflammatory TME may provide therapeutic benefit. We previously demonstrated in adults with recurrent glioblastoma that loco-regional delivery of interleukin 12 administered under the control of the proprietary transcriptional switch RheoSwitch Therapeutic Systemâ (RTSâ) delivered via a replication-incompetent adenovirus (“Controlled IL-12”) turned “cold” tumors “hot” for up to 5.8 months (Sci Transl Med. 2019;11(505)) and seemed to improve median overall survival as compared with historical controls (SNO 2020). A multicenter, phase I/II, open-label study (NCT03330197) is determining the safety and tolerability of Ad (2 x 1011 viral particles) administered by stereotactic intratumoral injection (Day 0) and 14 daily (Days 1 to 14) V doses (10 or 20 mg, body surface area adjusted). The first DIPG subject enrolled was in April 2020 with completion of the first cohort (arm 1, n=3) enrollment anticipated by September 2020. The first subject has tolerated treatment well with no SAEs during the evaluation period. Endogenous serum cytokines increased (including IFN-g 11.4 pg/mL, Day 3), consistent with V crossing the blood-brain barrier and activating the RTSâ switch to conditionally produce recombinant IL-12. Other biomarkers include plasma PK and circulating DNA. Follow-up is ongoing and enrollment is proceeding. Since development of effective immunotherapy for DIPG likely depends on eliciting a tumor-specific effector immune response, Controlled IL-12 is a promising immunotherapy candidate. The first DIPG subject shows encouraging data on safety, tolerability, serum cytokines and early signs consistent with a clinical response. After completion of dose-escalation, the study may be expanded up to 30 patients, which will be considered the phase II component of the study.
CTNI-06. SINGLE-CENTER REAL-WORLD ANALYSIS ON CEREBROSPINAL FLUID IN PATIENTS WITH LEPTOMENINGEAL METASTASES OF NON-SMALL CELL LUNG CANCER
Authors: Zhen Junjie , Wen Lei , Li Shaoqun , Lai Mingyao , Zhou Zhaoming , Shan Changguo , Cai Linbo 
Published: December 2020

Abstract

OBJECTIVE
To investigate the clinical values of real-world cerebrospinal fluid (CSF) examination in the diagnosis and prognosis of leptomeningeal metastases (LM) in the patients with non-small cell lung cancer (NSCLC).

METHODS
The clinical manifestations of patients diagnosed with NSCLC-LM in Guangdong Sanjiu Brain Hospital from 2010 until 2019 and the results from the routine, biochemical and cytologic examinations of their CSF were analyzed retrospectively. Moreover, the effects of different indicators on the prognosis of patients were determined by survival analysis.

RESULTS
Fifty-eight of the 80 patients underwent CSF examination, and the median values of the initial CSF pressure measured by lumbar puncture was 255mmH2O (60-350mmH2O). Tumor cells were found by the cytologic examination of CSF in 56 of the 58 cases (96.6%). The median levels of protein, glucose, chloride, lactate dehydrogenase (LDH) and carcinoembryonic antigen (CEA) in CSF were 0.4g/L (0–8.3g/L), 2.7mmol/L (0–11.9mmol/L), 120.7mmol/L (0–140.5mmol/L), 21.3U/L (0–221.5U/L) and 31.4ng/ml (0–784.2ng/ml), respectively. Sixteen patients underwent gene detection, and the results showed that there were 4 cases of wild type and 12 cases of mutation type. The survival analysis revealed that the median overall survival (mOS) after being diagnosed with LM, patients in LDH≤37U/L group and those in LDH &gt;37U/L group were 8.0 months, 23.7 months and 4.6 months (P=0.039), respectively, which indicated that the LDH level in CSF was the independent prognostic factor for the survival.

CONCLUSION
Using the cytologic examination of CSF in patients with LM to detect tumor cells is conducive to the early diagnosis of LM. The high CSF pressure in patients with LM is one of the reasons for the neurologic signs and symptoms. The gene mutations found in the CSF in some patients can be used to guide the further systematic treatment. The LDH level in CSF is the independent prognostic factor affecting the survival.
CTNI-07. DELIVERY AND ACTIVITY OF SN-38 BY SACITUZUMAB GOVITECAN IN CNS TUMORS
Authors: Brenner Andrew , Floyd John , Pandey Renu , Chiou Jennifer , Surapreneni Prathiba , Kaklamani Virginia , lathrop Kate , Crownover Richard , Caron Jean Louis , Tiziani Stefano 
Published: December 2020

Abstract

BACKGROUND
Sacituzumab Govitecan (SG, TRODELVY™) is an antibody drug conjugate, with payload and linker characteristics preferable for CNS delivery. SG utilizes a pH hydrolysable linker, allowing SN-38 to be released at the tumor site. SN-38 is the active component of Irinotecan and 1000-fold more potent than the parent compound. We observed SG activity in intracranial xenografts and hypothesized that SG would achieve therapeutically relevant concentration of SN-38 within the CNS.

METHODS
We performed a prospective, single center, window of opportunity trial (NCT03995706) to examine the intra-tumoral concentrations of SG, SN-38, and SN-38G in patients undergoing craniotomy for breast cancer brain metastases (BCBM, n=10) or recurrent glioblastoma (rGBM, n=10). Patients received a single dose of SG at 10mg/kg IV the day prior to craniotomy and tumor collected. [SN-38] was analyzed via mass spectrometry (UHPLC-HRMS). Patients resumed SG 10mg/kg IV days 1 and 8 of 21 day cycle following recovery and were assessed every third cycle by MRI using RANO criteria.

RESULTS
To date 16 patients have been treated, including 8 BCBM and 8 rGBM. UHPLC-HRMS analysis was performed in the first 10 tumors (n=4 and 6 respectively). For the rGBM patients, total concentration of SN-38 varied from 93nM to 680nM, with a mean concentration of 420nM. For BCBM, total concentration of SN-38 varied from 173nM to 1160nM, with a mean concentration of 626nM. All GBM patients had residual measurable disease and 4 breast patients had measurable disease. With a median follow-up of 12 weeks from the first postoperative cycle in the first 14 patients, 2 partial responses from each group were observed (ORR of 28% and 50% at 12 weeks respectively).

CONCLUSIONS
SG achieves therapeutically relevant concentrations of SN-38 at 40-fold mean IC50s for GBM, and 150-fold mean IC50s for BCBM. Early intracranial responses are encouraging and merit further evaluation.
CTNI-10. MAINTENANCE CHEMOTHERAPY USING BEVACIZUMAB FOR NEUROFIBROMATOSIS 2 PATIENTS WITH HEARING LOSS AND PROGRESSIVE VESTIBULAR SCHWANNOMAS: AN NF CLINICAL TRIALS CONSORTIUM STUDY (NF104)
Authors: Plotkin Scott , Tonsgard James , Ullrich Nicole , Allen Jeffrey , Blakeley Jaishri , Dhall Girish , Campian Jian , Clapp Wade , Fisher Michael , Cutter Gary , Korf Bruce , Packer Roger , Thomas Coretta , Edwards Lloyd , Karajannis Matthias 
Published: December 2020

Abstract

BACKGROUND
Bevacizumab treatment at 2.5–5 mg/kg/week is associated with hearing improvement and tumor shrinkage in about 40% of patients with neurofibromatosis 2 (NF2) and progressive vestibular schwannomas (VS). Treatment-emergent hypertension and proteinuria are common with prolonged treatment, and data supporting strategies to maintain hearing and minimize toxicity are lacking.

METHODS
We conducted a multicenter, phase II, open-label study of bevacizumab for subjects (≥6 years old) with NF2, hearing loss, and progressive VS. After 6 months of induction therapy (10 mg/kg every 2 weeks), subjects received low dose bevacizumab at 5 mg/kg every 3 weeks during maintenance therapy (18 months). Hearing decline was defined as a significant decrease in word recognition score below baseline. Progressive disease was defined as ≥20% increase in tumor volume from baseline.

RESULTS
Twenty of 22 subjects (median age=23 years) were treated with maintenance bevacizumab. The proportion of subjects free from hearing decline at 6, 12, and 18 months was 88%, 94%, and 85%, respectively; the proportion free from tumor progression at 6, 12, and 18 months from baseline was 88%, 94%, and 85%, respectively. Three subjects (15%) experienced hearing loss during maintenance and required dose escalation. Maintenance chemotherapy with bevacizumab was well tolerated: 1 subject discontinued due to perirectal abscess and 2 discontinued by choice. Grade 3 hypertension occurred in 2 subjects (10%). Adverse events of interest included hypertension (55%), proteinuria (20%), and irregular menstruation (6/13, 46%).

CONCLUSIONS
Maintenance chemotherapy with bevacizumab at 5 mg/kg every 3 weeks is associated with prolonged hearing and tumor stability that surpasses historical controls. A minority of subjects require dose escalation during low dose bevacizumab treatment.
CTNI-18. FINAL RESULTS OF A PHASE 2 STUDY OF EFFICACY, SAFETY AND INTRATUMORAL PHARMACOKINETICS (PK) OF SELINEXOR MONOTHERAPY IN RECURRENT GLIOBLASTOMA (rGBM)
Authors: Lassman Andrew , Wen Patrick , van den Bent Martin , Plotkin Scott , Walenkamp Annemiek , Green Adam , Wang Hongwei , Li Kai , Liu Yang , Xu Hongmei , Shah Jatin , Kauffman Michael , Shacham Sharon , Mau-Soerensen Morten 
Published: December 2020

Abstract

BACKGROUND
Selinexor is an FDA-approved first-in-class, oral selective nuclear export inhibitor which forces nuclear retention of many tumor suppressor proteins.

METHODS
We conducted a phase 2 trial of selinexor monotherapy for adults with recurrent GBM including a surgical arm to explore intratumoral PK and 3 medical arms to optimize dosing. Prior treatment with radiotherapy and temozolomide was required; prior bevacizumab was exclusionary. The primary endpoint was 6-month progression-free survival (6mPFS) rate.

RESULTS
Selinexor administered ~2 hours pre-operatively yieleded average intratumoral concentration (136 nM, n=6) comparable to the in vitro IC50 (130 nM) from 7 primary human GBM cell lines. Among all 68 patients accrued to 3 medical arms (~85 mg BIW, n=24; 60 mg BIW, n=14; 80 mg QW, n=30), median age was 56 years (21–78). Median number of prior lines of therapies was 2 (1–7). At 80 mg QW, 28% patients were progression-free at the end of cycle 6; the 6mPFS was 17%; disese control rate by RANO was 37% (1 CR, 2 PRs, 7 SD) among 27 evaluable patients; responses were durable (median 11.1 months), and treatment lasted for 442, 547 and 1282 days in 3 responders, as of data lock, with one responder remaining on treatment off study; median overall survival was 10.2 months with 95% CI (7.0, 15.4). The ~85 mg BIW-schedule was abandoned due to poor tolerability. The related adverse events (all grades) in patients on ~85 mg BIW/60 mg BIW/80 mg QW were nausea (41.7%/64.3%/66.7%), fatigue (70.8%/71.4%/50.0%), neutropenia (29.2%/14.3%/33.3%), decreased appetite (45.8%/71.4%/26.7%), thrombocytopenia (66.7%/28.6%/23.3%) and weight loss (16.7%,/42.9%/6.7%).

CONCLUSION
Selinexor monotherapy demonstrated encouraging intratumoral penetration and efficacy, with durable disease control in rGBM. Monotherapy dose at 80 mg QW is recommended for further development in rGBM. A phase 1/2 study of combination therapy for newly diagnosed or rGBM has been initiated (NCT04421378).
CTNI-19. PHASE I TRIAL OF DAY101 IN PEDIATRIC PATIENTS WITH RADIOGRAPHICALLY RECURRENT OR PROGRESSIVE LOW-GRADE GLIOMA (LGG)
Authors: Wright Karen , Krzykwa Emily , Greenspan Lianne , Chi Susan , Yeo Kee Kiat , Prados Michael , Mueller Sabine , Haas-Kogan Daphne 
Published: December 2020

Abstract

BACKGROUND
We report phase I data examining pharmacokinetics, safety and preliminary efficacy of the dimeric, pan-RAF inhibitor DAY101 (formerly TAK-580/MLN2480) in pediatric patients with radiographically recurrent/progressive LGGs harboring MEK/ERK pathway alterations.

METHODS
Oral DAY101 was administered weekly to patients &lt; 18 years of age with radiographically recurrent/progressive LGG for 4-week cycles up to a maximum of 2 years. The starting DAY101 dosage was 280 mg/m2. Dose limiting toxicities were determined after one cycle.

RESULTS
We treated nine eligible patients at 280, 350, and 420 mg/m2. Seven patients had KIAA1549:BRAF fusions, one a novel SRGAP3-RAF1 gene fusion and one with NF1 mutation. PK parameters following weekly administration of DAY101 in children mirrored the adult data, with dose-proportional increases in Cmax and AUC observed. There were no DLTs. The most common toxicity was skin rash followed by achromotrichia and nevi formation. There was only one grade 3 elevation is CPK and no grade 4 adverse events. A 2.2-fold mg/kg exposure difference was observed with respect to weight-based dosing and suggested a correlation to independent, centrally reviewed best radiographic RANO responses of 2 complete responses, 2 partial responses, 3 stable disease, and 2 progressive disease. Median time to response was 10.5 weeks (range: 8–32 weeks).

CONCLUSIONS
These phase 1 data provide initial pharmacokinetic parameters outlining oral weekly dosing of DAY101 in pediatric patients with radiographically recurrent and progressive LGG. Plasma exposures of DAY101 are similar in children and adults. Oral weekly DAY101 is well-tolerated and shows anti-tumor activity. The amended protocol explores differential dosing to achieve similar responses across a variety of body surface areas.
CTNI-20. PCV CHEMOTHERAPY ALONE IS ASSOCIATED WITH BETTER CLINICAL COURSE IN OLIGODENDROGLIOMA WHO GRADE II
Authors: Weller Jonathan , Katzendobler Sophie , Karschnia Philipp , Lietke Stefanie , Egensperger Rupert , Thon Niklas , Weller Michael , Kreth Friedrich-Wilhelm , Suchorska Bogdana , Tonn Joerg-Christian 
Published: December 2020

Abstract

BACKGROUND
Current treatment guidelines for oligodendrogliomas (OD) recommend watch-and-wait strategies after gross total resection and radiation with subsequent chemotherapy (procarbazine, CCNU and vincristine (PCV)) after incomplete resection. The value of chemotherapy alone as an option to delay the risk of late cognitive deficits is not well defined yet. Here, we retrospectively investigated long-term outcome in OD WHO II with respect to initial therapy and tumor volume in magnetic resonance imaging (MRI).

METHODS
A total of 142 patients with OD WHO (World Health Organization) II according to WHO 2016 were retrospectively included. Patients either had watch and wait (W&W) after histological sampling through stereotactic biopsy (n=59) or tumor resection (n=27) or else stereotactic biopsy with subsequent temozolomide (TMZ) (n=26) or PCV (n=30). Pre- and post-therapeutic T2 tumor volumes were obtained. Progression-free survival (PFS), post-recurrence PFS (PR-PFS) and rate of secondary malignization after 10 years (MR-10yrs) were correlated with clinical and volumetric data.

RESULTS
PFS was significantly longer in the PCV cohort compared to TMZ (9.1 vs. 3.6 years, p = 0.04), even after matching patients according to age and initial tumor volume (9.1 vs 4.7 yrs, p = 0.03). PFS in the W&W cohort was 5.1 years and 4.4 years in those receiving tumor resection only. MR-10yrs was 4% in PCV cohort, 18% in the W&W cohort and 52% in the resection only cohort (p = 0.01). In the W&W cohort, patients treated with PCV at first relapse had a longer PR-PFS than those treated with TMZ (in years, 7.2 vs 4.0, p = 0.04). Multivariate analysis confirmed initial PCV therapy (p = 0.01) and initial T2 tumor volume (p = 0.02) to be prognostic.

CONCLUSION
In oligodendrogliomas WHO II PCV chemotherapy alone is superior in terms of PFS and rate of secondary malignization compared to TMZ chemotherapy alone or tumor resection only.
CTNI-28. A PROSPECTIVE, OBSERVATIONAL STUDY EVALUATING THE SAFETY AND QUALITY OF LIFE OF TUMOR TREATING FIELDS IN CHINESE GLIOBLASTOMA PATIENTS
Authors: Wong Kevin , Jiang Tao 
Published: December 2020

Abstract

OBJECTIVES
Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median survival of 15 months. Adding Tumor Treating Fields (TTFields) to first-line therapy in GBM demonstrated improved survival in the EF-14 trial. This prospective study was designed to investigate the safety and effect on QoL of TTFields in Chinese patients with GBM.

METHODS
A total of 44 patients (29 newly diagnosed GBM, 15 recurrent GBM, median age 51.0 [24.0 - 81.0] years) who underwent TTFields following surgery, concurrent chemoradiotherapy were enrolled into the study. The primary endpoint was the incidence of TTFields-related skin adverse events; the secondary endpoint included quality of life (QoL), treatment adherence.

RESULTS
Of the 44 patients followed up for at least 3 months, 24 (54.5%) had skin adverse reactions, all of which were grade 1–2. Median time to skin AE was 1.2 months. The common skin AE were dermatitis (53.8%), ulcer (19.2%), infection (19.2%), and most of them could be resolved by symptomatic treatment (topical corticosteroid/antibiotics). In terms of QoL, noticeable improvement in overall health and clinical manifestations such as fatigue, nausea and vomiting were observed. The overall average treatment compliance was 91%: compliance (mean±SD), in newly diagnosed patients, 0.89±0.14, median 0.91; in recurrent patients, 0.86±0.13, median 0.93.

CONCLUSIONS
The incidence of skin adverse reactions (which could be effectively alleviated with treatment) in GBM patients treated with TTFields was acceptable. From our short follow up, TTFields appear to improve QoL and compliance in Chinese patients comparable to published data.
CTNI-30. THERAPEUTIC EFFECTS OF RADIOTHERAPY WITH CONCOMITANT AND ADJUVANT TEMOZOLOMIDE VERSUS RADIOTHERAPY WITH CONCOMITANT TEMOZOLOMIDE ALONE IN CHILDREN WITH DIPG: A SINGLE-CENTER EXPERIENCE WITH 82 CASES
Authors: Lai Mingyao , Li Juan , Hu Qingjun , Zhou Jiangfen , Li Shaoqun , Wen Lei , Cai Linbo 
Published: December 2020

Abstract

OBJECTIVE
To retrospectively analyze the therapeutic effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy with concomitant temozolomide alone for pediatric diffuse intrinsic pontine glioma (DIPG), and to evaluate the value of temozolomide in the treatment of pediatric DIPG.

METHODS
The clinical data of children with confirmed DIPG in Guangdong Sanjiu Brain Hospital between January 1, 2010 and December 30, 2019 were collected. The inclusive criteria included (1) receiving a total radiotherapy dose of 54 Gy in 27 fractions, (2) treated with concomitant temozolomide chemotherapy, and (3) with or without adjuvant temozolomide chemotherapy.

RESULTS
A total of 82 pediatric patients were eligible for the study, with a median age of 7 years (range 2–16 years). The median follow-up was 8.6 months (range 2–28 months) and the median survival time was 9.4 months. The median survival time of 66 patients treated with radiotherapy with concomitant and adjuvant temozolomide was 9.8 months, longer than 7.5 months of the other 16 patients treated with radiotherapy with concomitant temozolomide alone, with statistical differences (P=0.010). Moreover, bevacizumab and nimotuzumab didn’t bring survival benefits to patients with disease recurrence or progression. Hematological toxicity (Grade IV) was not found.

CONCLUSION
Radiotherapy with concomitant and adjuvant temozolomide prolongs the survival time of children with DIPG.
CTNI-36. TREATMENT AND PROGNOSTIC FACTORS FOR PEDIATRIC GLIOBLASTOMAS--THE 10 YEARS EXPERIENCE FROM ONE SINGLE CENTER
Authors: Li Juan , Lai Mingyao , Hu Qingjun , Zhou Zhaoming , Zhang Xing , Cai Linbo 
Published: December 2020

Abstract

OBJECTIVE
We retrospectively analyzed the clinical features of pediatric glioblastoma patients in our center in the past 10 years.

METHODS
From November 2009 to December 2018, patients with glioblastoma under 18 years were admitted to Guangdong Sanjiu Brain Hospital. Clinical and pathological features were summarized, and the curative effect was evaluated.

RESULTS
A total of 31 pediatric patients were enrolled. The median age is 13.8 years (range 0.8–18), including 19 males and 12 females. To Sep, 2019, the median follow-up time was 18 months(Range 4–80 months). Among them, 2 were lost to follow-up, 13 died, 16 still survived, and the longest survivor survived for 80 months. The median survival time was 16.4 months, the 2-year survival rate was 38%. In the prognostic factor analysis, the median survival time of patients with surgical resection ≥90% was 18 months (95% CI 15.9–20 months), and for children with resection 90% was 11 months (95% CI 9.9–12 months), P=0.027, with significantly statistically difference. Multivariate analysis showed that tumor resection rate was an independent prognostic factor for survival.

CONCLUSION
The prognosis of pediatric glioblastoma is still dismal. This study demonstrates that prognosis of such patients with GTR or near GTR is better.
CTNI-39. PHASE 1B CLINICAL TRIAL OF OKN-007 IN RECURRENT MALIGNANT GLIOMA
Authors: Battiste James , Ikeguchi Alexandra , Woo Sukyung , Sharan Satish , Zhao Yan , Cohoon Andrew , Sung Sarah , Wright Deborah , Teague April , Jensen Randy , Kim Eun Ha , Yang Won , Towner Rheal 
Published: December 2020

Abstract

BACKGROUND
The nitrone compound OKN-007 is a novel anti-cancer agent. In glioblastoma xenografts, OKN-007 reduces cell proliferation and angiogenesis, and increases apoptosis. Here we report on the safety, efficacy, and pharmacokinetics (PK) of OKN-007 in adults with recurrent glioma.

METHODS
NCT01672463 is a phase 1b trial of OKN-007 in adults with recurrent gliomas previously treated with standard therapy. OKN-007 was administered by IV. The study comprised a 3 + 3 dose escalation design followed by an expansion cohort at the maximum tolerated dose (MTD). The dose escalation drug levels were 20 (n = 3), 40 (n = 3), and 60 mg/kg (n = 3), treating on a schedule of thrice weekly for 4 weeks, then twice weekly for 4 weeks, then once weekly until progression. Drug PK was determined in the dose escalation cohorts. The expansion cohort was treated with 60 mg/kg thrice weekly for 12 weeks, then twice weekly for 12 weeks, then once weekly until progression (n = 6). Kaplan-Meier analysis was used to determine progression-free (PFS) and overall survival (OS).

RESULTS
Median age was 51 years (range, 25–62). No dose-limiting toxicities were observed. The expansion dose was 60 mg/kg. Of 123 adverse events (AEs), 34 were deemed probably (1.6%) or possibly (26%) treatment-emergent (TEAE). The most commonly-occurring TEAEs were fatigue (4.1%) and headache (3.3%). Grade 3 TEAEs included headache, urinary tract infection, and increased prothrombin time (0.8% each). Two grade 1 AEs, hypokalemia and dizziness, were considered probably attributable to OKN-007. In patients receiving 60 mg OKN-007/kg, median PFS was 1.4 months and OS was 21 months (log rank p = 0.08 for comparison across doses). Systemic PK exposure was dose proportional. The average half-life of OKN-007 is 2.8 hours.

CONCLUSIONS
OKN-007 appears safe and, compared to standard therapy, may prolong OS in recurrent glioma.