bluuebunny/crossref_metadata_2025 huggingface dataset:
CTIM-02. TWO OUNCES OF PREVENTION: A SYSTEMATIC REVIEW AND META-ANALYSIS OF VEGF AND IMMUNE CHECK POINT INHIBITION FOR PRIMARY AND SECONDARY PREVENTION OF BRAIN METASTASES
Authors: Mansouri Alireza , Mansouri Alireza , Brown Timothy , Aregawi Dawit , Zacharia Brad , Glantz Michael
Published: December 2020

INTRODUCTION

As treatments for cancer outside of the central nervous system improve, brain metastases (BMs) are becoming increasingly frequent. Despite novel treatment options, BMs remain a frequent cause of death for many advanced malignancies, and both the metastases and their treatments are associated with profound cognitive, quality of life, and economic costs.

METHODS

We conducted exhaustive, PRISMA-compliant systematic reviews of the literature from January 2000 to June 2020 for studies comparing the frequency of new BM in patients treated with chemotherapy regimens including and not including bevacizumab (“primary prevention”), and for studies comparing the frequency of new outside-of-treatment-field metastases in patients treated with stereotactic radiosurgery (SRS) with or without immune checkpoint inhibitors (“secondary prevention”). Pre-specified data was extracted and summary statistics were calculated using the inverse variance method and random effects model.

RESULTS

Seven studies (n=6,212) reported on BMs in breast, lung, and colon cancer patients treated with chemotherapy with or without bevacizumab. The relative risk (RR) and 95% confidence intervals [95% CI] for the development of new brain metastases was 0.71 [0.55–0.91, p=0.001]. A sensitivity analysis performed on the 3 breast cancer trials (n=2,350) showed a RR of 0.57 [0.34–0.94, p=0.027]. Seven studies (n=609) reported on patients with melanoma BM receiving SRS without or without an ICI. The RR for the development of new out-of-treatment field brain metastases was 0.70 [0.51–0.94, p=0.017]. Results were similar in sensitivity analyses examining only class I and class II trials.

CONCLUSION

This analysis suggests that the addition of bevacizumab to chemotherapy or ICI SRS+/- chemotherapy can reduce the development of first-ever or new BM by 30% in patients with advanced stage breast, lung, or colon cancer. Prospective trials of primary and secondary prevention in patient groups at high risk of developing BMs, and examining additional predictors of response, are currently underway.
CTIM-23. A PHASE 1 TRIAL OF D2C7-IT IN COMBINATION WITH ATEZOLIZUMAB IN RECURRENT WHO GRADE IV MALIGNANT GLIOMA (MG)
Authors: Desjardins Annick , Randazzo Dina , Chandramohan Vidya , Peters Katherine , Johnson Margaret , Landi Daniel , Khasraw Mustafa , Threatt Stevie , Bullock Chevelle , Herndon James , Lipp Eric , Sampson John , Friedman Allan , Friedman Henry , Ashley David , Bigner Darell
Published: December 2020

BACKGROUND

D2C7 immunotoxin (D2C7-IT) is a dual-specific recombinant immunotoxin comprising an EGFR-wt and mutant-specific (EGFRvIII) monoclonal antibody fragment and a genetically engineered form of the pseudomonas exotoxin. When injected directly into the tumor mass by convection enhanced delivery (CED), in addition to direct tumor cell killing, immunotoxins induce secondary immune responses by the activation of CD4+ and CD8+ T-cells. We completed a phase 1 dose escalation study of D2C7-IT injected by CED into recurrent WHO grade III-IV MG and identified the phase 2 dose (6,920 ng/mL). Three patients remain in partial response more than 58, 38, and 32 months after a single D2C7-IT intratumoral infusion. As optimal induction of anti-tumor immune responses by immunotoxins is impeded by potent MG-mediated immunosuppression, we are assessing the toxicity of the combination of D2C7-IT with atezolizumab in patients with recurrent WHO grade IV MG.

METHODS

Eligibility includes adult patients with recurrence of a solitary supratentorial WHO grade IV MG; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS >70%. Patient receives an intratumoral infusion of D2C7-IT and initiates two weeks later atezolizumab at 1200mg, followed by atezolizumab every 3 weeks for up to 2 years. Two cohorts of 3 patients are initially accrued to assess the toxicity of the combination. Assuming accrual continues after the initial two cohorts of 3 patients, an additional 12 patients will be accrued to the study.

RESULT

The first enrolled patient experienced a grade 3 DLT (grade III ALT elevation) after the first infusion of atezolizumab, but showed a more extensive immunotherapeutic effect by imaging than observed with patients on the D2C7-IT monotherapy trial. Enrollment is ongoing.

CONCLUSION

D2C7-IT monotherapy has shown prolonged survival and disease control in some patients. We are now evaluating the combination of D2C7-IT with checkpoint inhibition.
CTIM-25. ONCOLYTIC VIRUS FOR DIPG: THE CLINICAL EXPERIENCE WITH DNX-2401
Authors: M Alonso Marta , Iñigo-Marco Ignacio , Garcia-Moure Marc , González-Huarriz Marisol , Jones Chris , MACKAY Alan , Hulleman Esther , Van der Lugt Jasper , De Andrea Carlos , Villalba Maria , Hernandez Ruben , Hervás Sandra , Tamayo Ibon , Lang Frederick , Gomez-Manzano Candelaria , Fueyo Juan , Diez-Valle Ricardo , de Larraya Jaime Gállego-pérez , Tejada Sonia
Published: December 2020

Despite our increased understanding of Diffuse Intrinsic Pontine Glioma (DIPG) the outcome remains dismal. Recently we showed that the virus Delta-24-RGD (DNX-2401 in the clinic) was effective in preclinical models of DIPG and had the ability to trigger an antitumor immune response. These data allowed us to propel a phase I clinical trial for newly diagnosed DIPGs (NCT03178032) where the patients received an intratumoral viral injection followed by standard radiotherapy. The main objective is to determine the safety, tolerability, and toxicity of DNX-2401. Secondary endpoints are overall survival at 12 months, percentage of responses and induced immune response against tumor. Tumor biopsy was performed through the cerebellar peduncle, followed by intratumoral injection of DNX-2401 (N=12). Three patients were treated with the D1=1x1010vp and because the lack of toxicity we escalated to the D2= 5x1010vp. The procedure was well tolerated and safe. All patients displayed a reduced tumor volume after combined treatment. We performed molecular studies in 9 out of the 12 patients. The immune cell composition of the biopsies was assessed using multiplexed quantitative immunofluorescence. T cells were hardly noticeable in these tumors while macrophages were abundant. We detected increased clonal T cell diversity following treatment with virus in peripheral blood lymphocytes when compared paired pre- and post-treatment samples from the trial. In addition, we measure pre and post treatment neutralizing antibodies and its relationship with survival. Finally, we performed functional studies using 2 cell lines isolated from patients included in this trial to assess the response to the virus (infectivity, viability, T-cell recognition). Overall, the administration of DNX2401 was safe, feasible and therapeutically beneficial in a subgroup of patients. This trial constitutes a proof of principle that aids to understand the response of DIPGs to viral therapies allowing to set the bases to improve this strategy for DIPG.
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

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

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 >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

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

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

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

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 < 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

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

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

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

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

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.
CTNI-44. INTERIM RESULTS OF PHASE 2 STUDY TO EVALUATE PI3K/mTOR INHIBITOR PAXALISIB (GDC-0084) GIVEN TO NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS WITH UNMETHYLATED O6-METHYLGUANINE-METHYLTRANSFERASE PROMOTER
Authors: Wen Patrick , de Groot John , Battiste James , Goldlust Samuel , Damek Denise , Garner James , Simpson Jeremy , Olivero Alan , Cloughesy Timothy
Published: December 2020

BACKGROUND

Paxalisib (GDC-0084) is a potent, oral, selective small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin (PI3K/mTOR). Paxalisib crosses the blood-brain barrier and achieves a brain / plasma ratio of approximately 1.0. An MTD of 60mg per day has been identified in newly diagnosed glioblastoma (GBM) patient with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status. Paxalisib has shown encouraging indications of clinical activity.

METHODS

This study has a 2-part design: an open-label, dose-escalation phase (Stage 1) to define MTD, followed by an expansion cohort (Stage 2) at the MTD and patients are randomized to take paxalisib, in fed or fasted states. Pharmacokinetic data will be analysed and compared by dose and fed/fasted status.

RESULTS

Stage 2 (expansion cohort) is fully enrolled and patients are in follow-up. Adverse event profile seems broadly consistent with prior clinical experience and with other PI3K-targeting agents. With analysis including all patients, a sustained PFS signal of 8.5 months is seen and this compares favourably with historical controls.

CONCLUSION

Paxalisib displays a safety profile consistent with previous data and promising efficacy signals in newly diagnosed GBM. A pivotal study in GBM is planned to commence recruitment later this year.
CTNI-62. CLINICAL FEATURES AND PROGNOSTIC FACTORS OF NONGERMINOMATOUS GERM CELL TUMORS IN 111 CONSECUTIVE PATIENTS IN A SINGLE INSTITUTION: IMPACT OF IRRADIATION AND CHEMOTHERAPY CYCLES ON SURVIVAL
Authors: Wen Lei , Li Juan , Hu Qingjun , Lai Mingyao , Zhou Cheng , Shan Changguo , Cai Linbo
Published: December 2020

BACKGROUND

Limited data is available in intracranial nongerminomatous germ cell tumors (NGGCTs) in Chinese population. Here we aimed to retrospectively assess the clinical-pathological and prognostic factors of NGGCTs in a single large institution in China.

METHODS

From June 2003 to December 2018, 111 consecutive NGGCTs were treated in Guangdong Sanjiu Brain Hospital, China.

RESULTS

The median follow-up was 36.2 months (range, 1.2 to 131.2 months). Three-year EFS and OS for 111 NGGCTs patients were 78.5%±4.5% and 82.8%±4.0%, respectively. 98 patients received CSI plus boost yielded better survival than those who received reduced-volume radiotherapy or no radiotherapy (3y OS, 86.7% vs. 51.4%, p=0.007). Patients had at least four cycles of chemotherapy were strongly associated with improved 3-year OS, compared to those received less than 4 cycles (94.1% vs. 63.6%, p＜0.001). There was no significant difference in survival of patients stratified by age, surgery, hydrocephalus, as well as tumor diameter. Multivariate analysis identified chemotherapy cycles less than 4 was the only prognostic factor that conferring a worse OS (p=0.003). Patients both received CSI and at least 4 courses of chemotherapy were correlated with lower incidence of relapse (p=0.044).

CONCLUSIONS

Multimodal approach including CSI and enough courses of chemotherapy was effective and should be recommended for the treatment of newly diagnosed NGGCTs in Chinese population.
CTNI-70. LONG-TERM SURVIVAL IN GLIOBLASTOMA PATIENTS AFTER TUMOR TREATING FIELDS (TTFIELDS) THERAPY
Authors: Rulseh Aaron , Derner Adam , Sroubek Jan , Klener Jan , Vymazal Josef
Published: December 2020

PURPOSE

Glioblastoma multiforme (GBM) is the most common and malignant primary intracranial tumor and traditionally has a median survival of only 10 to 14 months, with only 3 to 5% of patients surviving more than three years. Recurrence (RGBM) is nearly universal, and further decreases the median survival to only 5 to 7 months with optimal therapy. Thus, advances in treatment that may improve survival in these patients are highly desirable.

METHODS

Tumor treating fields (TTFields) therapy (Novocure Ltd., Haifa, Israel) is an approved antimitotic treatment for patients with newly diagnosed and recurrent GBM. TTFields are low-intensity (1–3 V/cm), intermediate-frequency (100–300 kHz) alternating electric fields that selectively kill or arrest the growth of rapidly dividing cells by inhibiting the proper formation of the mitotic spindle and by causing rapid membrane breakdown during cytokinesis.

RESULTS

Our center was the first in the world to apply TTFields treatment to histologically proven GBM in a pilot study of 20 individuals (10 GBM and 10 RGBM) in 2004 and 2005, and 4 of the original 20 patients are still alive today (2 GBM, 2 RGBM), in good health and no longer receiving any treatment roughly 15 years (range 14.2–15.9 years) after initiating TTFields therapy, with no clinical or radiological evidence of recurrence. The diagnosis of GBM was confirmed in all patients in two independent laboratories. Two of the 4 surviving patients exhibited radiological signs of tumor growth initially, before the tumor regressed in size after a median of 4 months of continuous treatment.

CONCLUSIONS

Our results indicate that TTFields treatment may be remarkably successful for both newly diagnosed and recurrent GBM patients. We recommend that TTFields treatment should be applied for a sufficient amount of time, and that initial radiologic progression following treatment initiation should not be considered a reason to discontinue treatment.
DDRE-10. IMMUNE PROFILES ASSOCIATE WITH OUTCOMES IN HLA-A*02:01+, H3.3K27M+ PATIENTS WITH DIFFUSE MIDLINE GLIOMAS TREATED WITH H3.3K27M PEPTIDE VACCINE COMBINED WITH POLY-ICLC: A PNOC REPORT
Authors: Mueller Sabine , Taitt Jared M , Villanueva-Meyer Javier , Bonner Erin R , Nejo Takahide , Lulla Rishi R , Goldman Stewart , Banerjee Anurhada , Chi Susan , Whipple Nicholas S , Crawford John R , Gauvain Karen , Nazemi Kellie , Watchmaker Payal , Almeida Neil D , Okada Kaori , Salazar Andres , Gilbert Ryan , Nazarian Javad , Molinaro Annette , Butterfield Lisa H , Prados Michael , Okada Hideho
Published: December 2020

BACKGROUND

Patients with diffuse midline gliomas (DMG), including diffuse intrinsic pontine glioma (DIPG), have dismal outcomes. We previously described the H3.3K27M mutation as a shared neoantigen in HLA-A*02.01+ H3.3K27M+ DMGs. Within the Pacific Pediatric Neuro-Oncology Consortium, we assessed the safety and efficacy of an H3.3K27M-targeted peptide vaccine.

PATIENTS AND METHODS

Newly diagnosed patients aged 3–21 years with positive HLA-A*02.01+ and H3.3K27M+ status were enrolled into two strata after completion of radiation therapy: Stratum A for DIPG (n=19); Stratum B for non-pontine DMG (n=10). Vaccine was administered in combination with poly-ICLC every three weeks for eight cycles, followed by once every six weeks. Immunological responses were assessed in peripheral blood mononuclear cells using mass cytometry.

RESULTS

19 patients enrolled in Stratum A (median age=11 years) and 10 in Stratum B (median age=13 years). There were no grade 4 treatment-related adverse events (TRAE). Injection site reaction was the most commonly reported TRAE. Overall survival (OS) at 12 months was 40% (95% CI, 22% to 73%) for Stratum A and 39% (95% CI, 16% to 93%) for Stratum B. The median OS was 16.1 months in patients exhibiting an expansion of H3.3K27M-reactive CD8+ T-cells compared to 9.8 months for their counterparts (p=0.05). DIPG patients with below-median baseline levels of myeloid-derived suppressor cells had prolonged OS compared to their counterparts (p< 0.1). Immediate pre-treatment dexamethasone administration inversely associated with H3.3K27M-reactive CD8+ T-cell responses. However, neither tumor size or bulk CD8+ T-cell status was significantly associated with OS.

CONCLUSION

Administration of the H3.3K27M-specific vaccine is well tolerated. Patients with H3.3K27M-specific CD8+ immunological responses demonstrated prolonged OS compared to non-responders.
DDRE-11. DEVELOPMENT OF THE FIRST-IN-CLASS INHIBITOR OF CHD4 - SENSITIZING RESISTANT GLIOMAS
Authors: Nurmemmedov Elmar , Kesari Santosh
Published: December 2020

Glioblastoma is a lethal brain tumor with high recurrence rate. CHD4 overexpression, which drives resistance to DNA damage, is one of the major sources of recurrence. Since standard GBM treatments like radiation and temozolomide chemotherapy create DNA damage, inhibition of CHD4 offers a new therapeutic option for resensitizing GBM. CHD4 is a ubiquitously expressed ATP-dependent chromatin remodeler, which plays a crucial role in epigenetic regulation of gene expression and in DNA damage repair. Structurally, CHD4 contains an HMG-like domain, PHD domains, two chromodomains, a catalytic ATPase module, two domains of unknown function (DUF) and a C-terminal domain CHDCT2. Currently, no specific inhibitors targeting this chromatin remodeler have been reported yet. We aim to develop the first-in-class inhibitor targeting chromo-domain of CHD4. We have performed in silico screens to identify small molecules binding to the chromo-domains of CHD4. We present our growing in vitro data demonstrating biophysical properties and mechanism-of-action of these novel inhibitors. We expect that the experiments proposed here will result in the development of the first-in-class CHD4 inhibitor which can be used in the future not only to better study the physiological role of CHD4 but also to determine its potential as a novel targeted therapy for GBM.
DDRE-12. PNOC001 (NCT01734512): A PHASE II STUDY OF EVEROLIMUS FOR RECURRENT OR PROGRESSIVE PEDIATRIC LOW-GRADE GLIOMAS (pLGG)
Authors: Mueller Sabine , Aboian Mariam , Nazemi Kellie , Gauvain Karen , Yoon Janet , Minturn Jane , Leary Sarah , AbdelBaki Mohamed , Goldman Stewart , Elster Jennifer , Resnick Adam , Molinaro Annette , Phillips Joanna , Prados Michael , Haas-Kogan Daphne
Published: December 2020

OBJECTIVE

To estimate the 6-month Progression Free Survival (PFS6) associated with everolimus for progressive/recurrent pLGGs and to determine if activated PI3K/Akt/mTOR pathway as measured by positive phosphorylated-ribosomal protein S6 (p-RPS6) status was associated with response.

METHOD

Patients 3–21 years of age with recurrent or progressive pLGG were enrolled. Everolimus was administered orally at 5 mg/m2 daily. Tissue availability for molecular analysis was mandatory. Immunohistochemistry (IHC) for p-RPS6 was performed centrally. An adaptive Simon two-stage design was employed based on p-RPS6 status. Based on results of the first stage, enrollment in the second stage was either limited to pathway activated patients or open to all subjects.

RESULTS

From December 2012 to July 2019 a total of 65 subjects enrolled [median age 9 years (range 3–19); 43% female]. As of December 15, 2019 median number of treatment cycle is 8 (range 1–24); 7 patients remain on treatment. Toxicity profile is similar to published reports with rash and elevated lipid profiles as most common adverse events. PFS6 for the entire cohort is 63%; PFS6 is 64% for the activated and 61% for the non-activated patients. Central imaging review (n=52) revealed 1 partial response, 1 complete response, 33 stable disease, and 17 progressive disease at the end of study treatment. Initial molecular analysis identified BRAF alterations in 35/65 patients.

CONCLUSION

Everolimus is well tolerated and active in a subset of pLGGs. Ongoing analyses will assess predictive biomarkers of response and will be reported at the meeting.
DDRE-15. THE COMBINATION THERAPY OF PARP INHIBITOR AND TMZ IN DIFFUSE MIDLINE GLIOMA HARBORING H3 K27M-MUTANT
Authors: Ohba Shigeo , Hashizume Rintaro , Hirose Yuichi
Published: December 2020

Diffuse midline glioma harboring H3 K27M-mutant (DMG) is a newly defined entity, and the prognosis of DMG is very poor. Combined of radiotherapy and chemotherapy is a standard therapeutic approach, because surgical debulking for providing relief to patients is not an option. Temozolomide (TMZ) is often used for the treatment of gliomas. TMZ is an alkylating agent that adds a methyl group to DNA (O6-guanine, N7-guanine, and N3-adenine). TMZ-induced cytotoxicity is mainly derived from O6-methylguanine, which is repaired by O6-methylguanine DNA methyltransferase (MGMT). Unfortunately, most DMG lacks MGMT promoter hypermethylation, which contributes to less effectiveness of TMZ in DMG. Because N7-methylguanine and N3-methyladenine are repaired via base excision repair, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor combined with TMZ was considered to be effective to suppress the proliferation of DMG. The purpose of the study is to evaluate whether PARP inhibitor sensitizes DMG to TMZ. A patient-derived DMG cell line, SF8628, showed the expression of MGMT, resulted in resistant to TMZ. We evaluated the effects of multiple PARP inhibitors: talazoparib, olaparib, niraparib, A-966492 in SF8628 DMG cells. These PARP inhibitors suppressed the proliferation of SF8628 cells in a dose dependent manner. Moreover, PARP inhibitors enhanced TMZ-induced cytotoxicity in SF8628. The combined treatment of PARP inhibitor and TMZ induced apoptosis. These results would support a possibility that the combination treatment of PARP inhibitor and TMZ is an effective approach in DMG.
DDRE-27. LMNA-PRKDC AXIS PROMOTES CHEMORESISTANCE IN RECURRENT GBM BY STABILIZING DNA REPAIR FOCI
Authors: Saathoff Miranda , Shireman Jack , Savchuk Sol , Baisiwala Shivani , Park Cheol , James Charles , Ahmed Atique
Published: December 2020

Tumors in patients with recurrent GBM are resistant to standard therapies. Available models for testing experimental therapies to treat GBM are primarily derived from or representative of primary, untreated GBM. We have developed a clinically relevant model of recurrent, therapy-resistant glioblastoma (GBM6R) from a patient-derived xenograft (PDX) of primary glioblastoma (GBM6) that underwent multiple rounds of temozolomide (TMZ) treatment following intracranial engraftment in a host mouse. Initial characterizations of GBM6R revealed a significant decrease in sensitivity to TMZ both in vitro (p< 0.008) and in vivo (p=0.0079). An unbiased screen to identify proteins with altered expression in GBM6R, relative to treatment naïve GBM6, revealed nuclear lamina protein LMNA as highly expressed in GBM6R. From in silico analysis we found that high LMNA expression is associated with poor survival for GBM patients (p=0.0001, Gravendeel; p=0.0078, TCGA_GBM; p< 0.0001, CCGA; GlioVis). GBM5 and GBM43 PDX explant cultures treated with multiple doses of TMZ increased their expression of LMNA. We found that in TMZ treated and TMZ resistant tumors, that LMNA preferentially localizes to the nuclear lamina (p< 0.001), which is not observed in primary, untreated tumors (p< 0.005). Analysis of LMNA by immunoprecipitation revealed that LMNA interacts with DNA-PK and γH2AX. From these results, we hypothesize that LMNA may be acting to stabilize DNA damage foci at the nuclear periphery, which results in enhanced DNA repair. Our observations support the testing of selective DNA-PK inhibitors for treating GBM, which would inhibit TMZ-induced DNA damage repair, and enhance the cytotoxic effects of TMZ.
DDRE-29. SMOOTHENED-ACTIVATING LIPIDS DRIVE RESISTANCE TO CDK4/6 INHIBITION IN HEDGEHOG-ASSOCIATED MEDULLOBLASTOMA
Authors: Daggubati Vikas , Hochstelter Jordan , Bommireddy Ani , Choudhury Abrar , Krup Alexis , Kaur Pervinder , Tong Pakteema , Li Amy , Xu Libin , Reiter Jeremy , Raleigh David
Published: December 2020

BACKGROUND

Medulloblastoma is an aggressive pediatric brain tumor that is associated with misactivation of the Hedgehog (HH) pathway. Our lab has shown that CDK6, a critical activator of the cell cycle, is a direct transcriptional target of oncogenic HH signaling, and that inhibiting CDK6 blocks the growth of HH-associated medulloblastoma in mice. A clinical trial exploring the efficacy of CDK6 inhibition in medulloblastoma patients is underway, but prior attempts to target the HH pathway in medulloblastoma have been encumbered by resistance to molecular monotherapy. Thus, we sought to identify mechanisms of resistance to CDK6 inhibition in HH-associated medulloblastoma.

METHODS

We performed orthogonal CRISPR and CRISPR interference screens in HH-associated medulloblastoma cells treated with pharmacologic inhibitors of CDK6 in vitro, and RNA-sequencing of HH-associated medulloblastomas with genetic deletion of CDK6 in vivo. Mechanistic and functional validation of resistance pathways was performed using CRISPR interference, immunoblotting, immunofluorescence, genetics, and pharmacology. Lipid quantification was carried out by ultra-high performance liquid chromatography-tandem mass spectrometry.

RESULTS

Our results reveal that decreased ribosomal protein expression underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, leading to endoplasmic reticular (ER) stress and activation of the unfolded protein response (UPR). We show that ER stress and the UPR increase the activity of enzymes producing Smoothened-activating sterol lipids that sustain oncogenic HH signaling in medulloblastoma despite CDK6 inhibition. These discoveries suggest that combination molecular therapy against CDK6 and HSD11ß2, an enzyme producing Smoothened-activating lipids, may be an effective treatment for HH-associated medulloblastoma. In support of this hypothesis, we demonstrate that concurrent genetic deletion or pharmacological inhibition of CDK6 and HSD11ß2 additively blocks the growth of multiple models of HH-associated medulloblastoma in mice.

CONCLUSIONS

Smoothened-activating lipid biosynthesis underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, revealing a novel combination therapy to treat the most common malignant brain tumor in children.