bluuebunny/crossref_metadata_2025 huggingface dataset:
CSIG-24. TARGETED INHIBITION OF CDK5-MEDIATED REGULATION OF HUMAN ENDOGENOUS RETROVIRUS K (HML-2) ENVELOPE PROTEIN IN ATYPICAL TERATOID RHABDOID TUMOR
Authors: Doucet-O'Hare Tara , Rosenblum Jared , DiSanza Brianna , DeMarino Catherine , Atkinson Abigail , Malik Nasir , Steiner Joe , Pant Harish , Nath Avindra , Zhuang Zhengping
Published: November 2021

Atypical teratoid rhabdoid tumor (ATRT) is a pediatric brain tumor with a high mortality rate characterized by mutations in/ deletions of SWI/SNF matrix-associated actin-dependent regulator of chromatin sub-family B member 1 (SMARCB1). We previously showed that loss of SMARCB1 causes up-regulation and release of HML-2 subfamily of human endogenous retrovirus K envelope protein (HML-2 ENV), resulting in maintenance of pluripotency. Here, we investigated intracellular trafficking and release of HML-2 ENV. Further, we demonstrate two potential therapeutic strategies to decrease intracellular HML-2 ENV: 1) inhibition of calcium influx by ouabain, a cardiac glycoside toxic to neural stem cells, and 2) targeted inhibition of cyclin-dependent kinase 5 (CDK5), which is restricted to neurons by p35, its activator protein, by TP5. ATRT cell lines and tumor tissue obtained from patients were confirmed for SMARCB1 loss and increased HML-2 ENV. Cell viability and intracellular HML-2 ENV concentration were measured after treatment with ouabain and TP5 (CDK5 antagonist). We evaluated the calcium-mediated effect of ouabain on HML-2 intracellular concentration by treating the cells with ouabain, the calcium chelators calcimycin and EGTA, and calpeptin, a calpain inhibitor, which activates CDK5, and measuring HML-2 ENV and p35. We evaluated HML-2 ENV for a CDK5 consensus phosphorylation site and performed co-immunoprecipitation to evaluate direct interaction. We evaluated activity of CDK5 in ATRT cell lines by autoradiography. Both Ouabain and TP5 caused a decrease in cell viability in a dose-dependent manner. Further, ouabain treatment decreased HML-2 ENV intracellular concentration. We found that HML-2 ENV contains a consensus phosphorylation site for CDK5. We discovered that HML-2 ENV was bound to CDK5. We established that ATRT cell lines had hyperactive CDK5. Finally, we established that the effect of ouabain on HML-2 ENV was due to indirect inhibition of calcium-mediated activation of calpain and thus CDK5.
CSIG-25. BAI1/ADGRB1 REGULATES TGFβ1-INDUCED MESENCHYMAL SWITCH IN MEDULLOBLASTOMA
Authors: Osuka Satoru , Yang Liquan , Zhu Dan , Hashimoto Hideharu , Van Meir Erwin G
Published: November 2021

Medulloblastoma (MB) is the most common malignant brain tumor in children. MB tends to metastasize to the brain meninges and subarachnoid space and the spinal cord. Leptomeningeal metastasis is frequently found at initial diagnosis and leads to tumor relapse after standard treatment. Leptomeningeal metastasis remains a major challenge and is related with poor outcome. Acquiring a better knowledge of molecular defects underlying metastatic disease is essential for the development of effective therapies. Brain-specific Angiogenesis Inhibitor 1 (BAI1/ADGRB1) is a transmembrane receptor of the adhesion GPCR family widely expressed in normal brain, but its expression is lost in the majority of medulloblastoma through epigenetic silencing. We reported that BAI1 protects p53 from Mdm2-mediated degradation and regulate tumor growth in medulloblastoma (Zhu D. et al, Cancer Cell, 2018). However, it is unclear whether BAI1 loss is important for tumor invasion and the mesenchymal phenotype in MB. Microarray analysis of the published MB dataset revealed that low BAI1 mRNA expression correlates with poor outcome and with expression of many key mesenchymal genes, including Fibronectin1, SLUG, and TWIST1. Restoration of BAI1 expression in human MB cells suppresses mesenchymal gene expression in culture, and dramatically decreases brain tumor invasion. Mechanistically, we found that the N-terminal thrombospondin type 1 repeat (TSR#1) of BAI1 inhibits the maturation process of TGFβ1, a key growth factor involved in EMT. BAI1 is silenced epigenetically in MB cells by methylated CpG-binding protein MBD2, and its expression can be reactivated by KCC-07, a blood-brain barrier permeable MBD2 inhibitor. We found that restoration of BAI1 expression by KCC-07 treatment dramatically reduced tumor cell invasion of MB cells. These experiments demonstrate that epigenetic silencing of BAI1 is important for activation of the MB invasive phenotype through TGFβ1 pathway activation. Epigenetic targeting of this process by KCC-07 can reduce MB invasion.
RADT-02. FACTORS ASSOCIATED WITH NEW-ONSET SEIZURES AFTER STEREOTACTIC RADIOSURGERY FOR NEWLY DIAGNOSED BRAIN METASTASES
Authors: Srinivasan Ethan , Lerner Emily , Edwards Ryan , Haskell-Mendoza Aden , Huie David , Vaios Eugene , Adamson Justus , Fecci Peter
Published: November 2021

INTRODUCTION

Stereotactic radiosurgery (SRS) is a highly effective therapy for newly diagnosed brain metastases. Risk factors for new-onset seizures after SRS have not been well established. In this study, we aimed to characterize the variables predictive of seizure risk.

METHODS

Patients treated with SRS for newly diagnosed brain metastases were retrospectively reviewed at a single institution. Data on baseline demographics, radiation parameters, and clinical courses were collected.

RESULTS

120 patients without previous seizure history were identified. Median age was 65 years (56-70.8) and baseline KPS 90 (80-90). 16 (13%) patients developed new-onset seizures within 3 months of SRS. In analyses comparing patients with and without new-onset seizures, there was no association between new-onset seizures and baseline KPS(90:80, p=0.48), prior resection (31%:28%, p=0.76), prior WBRT (6%:10%, p=1), immunotherapy or chemotherapy within 1 month (31%:21%, p=0.52 and 56%:57%, p=1), primary tumor site (p=0.07), number of lesions (2.2:3, p=0.21), cerebellar (25%:37%, p=0.41) or brainstem involvement (19%:14%, p=0.71), irradiated maximum target diameter (2.8:2.0cm p=0.191), maximum target volume (7.6:2.9 cm3 p=0.133), total dose of radiation (25:20Gy, p = 0.12), or use of fractionation (56%:35%, p=0.11). However, there was a significant difference in the total irradiated target volume (11.6 vs. 3.8 cm3, p=0.019) and a trend toward increased post-treatment seizures among patients with a total irradiated volume greater than 10cm3 (20%:9%, p=0.11, OR 2.4 [0.85-6.4]). Patients with seizures were also more likely to have received steroids (69%:34%, p=0.012) and AEDs (28%:15%, p=0.021) prior to SRS.

CONCLUSIONS

Our data suggest that total treatment volume is associated with new-onset seizures within 3 months of SRS. The association between seizures and exposure to steroids or AEDs prior to SRS may be a surrogate for neurologic symptoms at presentation. Patients undergoing SRS to larger volumes and necessitating prophylactic steroids or AEDs may benefit from counseling or intensification of anti-seizure therapy.
RADT-06. RADIOTHERAPY FOR BRAIN METASTASES FROM THYROID CANCER: A RETROSPECTIVE COHORT STUDY
Authors: Blomain Erik , Berta Scott , Hug Nicholas , Giao Duc , Meola Antonio , Binkley Michael , Shahsavari Nastaran , Desai Kaniksha , Chang Steven , Soltys Scott , Pollom Erqi
Published: November 2021

PURPOSE/OBJECTIVE(S)

Brain metastases from thyroid carcinoma are rare. Although stereotactic radiosurgery (SRS) is a standard of care for patients with brain metastases across many histologies, the current NCCN guidelines do not support a universal role for this modality in thyroid cancer.

MATERIALS AND METHODS

Thyroid cancer patients with brain metastases treated with radiotherapy at our institution from 2002-2020 were studied. Cumulative risk of local failure, distant intracranial failure and radiation necrosis were calculated using a competing risk of death analysis and censored at the last imaging follow-up. Overall survival was analyzed using Kaplan-Meier method. Stratified cox regression was used to study per-lesion outcomes.

RESULTS

We identified 34 patients with 203 treated brain metastases. 179 (88.2%) lesions were of differentiated histology; the remainder were anaplastic histology. Four patients received whole brain radiotherapy (WBRT) while 30 patients received SRS (SFED 22, interquartile (IQ) range 20-22). Of the patients receiving WBRT, one (25%) had anaplastic histology, and the median number of lesions was 15 (as compared to 2 for SRS). Median follow up among survivors was 32.3 months and median survival was 10.8 months. There were no observed failures (local or distant intracranial) observed at 1 year in the 24 metastases with anaplastic histology, although competing risk of death was high (91.7%). The 1 year cumulative incidences of local failure and distant intracranial failures were 9.8% (95CI 5.7%-13.9%) and 35.0% (95CI 29.0%-41.0%), respectively, in differentiated tumors. 6 (10.2%) of the distant intracranial failures were new cases of leptomeningeal disease. The 1 year risk of radiation necrosis was 15.5%. Of these cases, most were Grade 2 (57.1%); 3 (42.9%) were Grade 4 (there were no Grade 1 or 3 events).

CONCLUSION

In the largest known cohort of thyroid cancer brain metastasis patients, radiotherapy and SRS appear to be safe and effective treatment modalities.
RADT-08. A VOLUMETRIC ANALYSIS OF STEREOTACTIC RADIOSURGERY LOW DOSE VOLUMES IN PREVENTING FUTURE BRAIN METASTASES
Authors: Shumway John , Yoon Won Sup , Tan Xianming , Schreiber Eric , Yanagihara Ted , Jaikumar Sivakumar , Sasaki-Adams Deanna , Quinsey Carolyn , Ewend Matthew , Das Shiva , Marks Lawrence , Shen Colette
Published: November 2021

PURPOSE/OBJECTIVE(S)

Stereotactic radiosurgery (SRS), compared to whole brain radiotherapy is limited in its ability to prevent development of brain metastases in untreated areas. The purpose of this study is to assess whether low-dose volumes delivered to uninvolved regions of the brain during SRS can reduce the risk of developing brain metastases in those regions.

MATERIALS AND METHODS

Data were collected for 69 patients with brain metastases who were treated with SRS at least two occasions. The regions of uninvolved brain receiving a high, intermediate, and low dose of incidental radiotherapy were defined as the volume receiving at least 10, 5, and 2.5 Gy if the prescribed dose was < 25 Gy (1-3 fraction plans) or the volume receiving at least 15, 7.5, and 5 Gy if the prescribed dose was ≥ 25 Gy (5 fraction plans). A second round metastasis was considered to occur within a given dose level if 20% or more of the tumor was found within that dose level. Probabilities were calculated based on the volume of each dose level as a percentage of total brain volume and were used to estimate the expected number of cases with at least one metastasis occurring in each dose level.

RESULTS

The average number of metastases treated in both rounds of SRS was two. The expected and observed number of cases with at least one second round metastasis were 0 and 2 for the high dose level (p=0.151), 7 and 3 for the intermediate dose level (p=0.018), and 17 and 11 for the low dose level (p=0.094).

CONCLUSION

We observed fewer than expected new metastases within prior SRS low dose levels based on volumetric probabilities, though this difference was only significant for the intermediate dose level. This suggests that low dose volumes from SRS may provide benefit in preventing future regional metastases.
RADT-09. ROLE OF RADIOTHERAPY IN MANAGEMENT OF PRIMARY SPINAL HIGH GRADE GLIOMA: A SINGLE INSTITUTION RETROSPECTIVE ANALYSIS
Authors: Upadhyay Rituraj , Khose Swapnil , Pokhylevych Halyna , Paulino Arnold dela Cruz , McAleer Mary Frances , Ghia Amol , Li Jing , Yeboa Debra Nana , Loghin Monica , Harrison Rebecca , O'Brien Barbara , Kamiya-Matsuoka Carlos , DeGroot John , Puduvalli Vinay , Tatsui Claudio , Prabhu Sujit , Zaky Wafik , Lin Frank , Weinberg Jeffrey , Rhines Laurence , Fuller Greg , Sandberg David , Johnson Jason Michael , McGovern Susan
Published: November 2021

BACKGROUND

Primary spinal high-grade gliomas(S-HGG) are rare, aggressive tumors and radiation therapy(RT) plays a dominant role in the management given their infiltrative nature. We conducted a single-institution retrospective review to study the clinicopathological features and management of S-HGGs.

METHODS

Patients with biopsy-proven S-HGG who received RT from 2001-2020 were analyzed for patient, tumor, and treatment characteristics. Kaplan-Meier estimate and Cox proportional hazard regression method were used for survival analyses.

RESULTS

Twenty-nine patients were identified with a median age of 25.9 years (range 1-74y). Four patients had gross total resection(GTR) while 25 underwent subtotal resection or biopsy. Nineteen patients had WHO grade 4 tumor. IDH1 mutation and MGMT promoter methylation were analyzed in 14 and four patients respectively; all were IDH wildtype and MGMT-promoter unmethylated. H3K27M mutation was present in five out of 10 patients tested. Twenty-two patients received photon-based radiation and 7 received proton therapy. Median RT dose was 50.4 Gy (range 39.6-54Gy) with 79% receiving >45Gy. 65% patients received concurrent chemotherapy, most commonly temozolomide. Twenty-three (79%) patients had documented recurrence. Overall, 16 patients relapsed locally, 10 relapsed in the brain and 8 developed leptomeningeal disease; only 8(35%) had isolated local relapse. Median OS from diagnosis was 21.3 months and median PFS after RT was 9.7 months. On univariate analysis, age, sex, GTR, grade, RT modality, RT dose and concurrent chemotherapy did not predict for survival. Patients with H3K27M mutation had a poorer median PFS after RT compared to those without the mutation but the difference did not reach statistical significance (p = 0.26).

CONCLUSIONS

Although 86% of patients had gross disease at RT and received a lower median RT dose than typically used in cerebral high-grade gliomas, only 55% of patients failed locally. H3K27M mutation may portend worse survival; future studies to improve the therapeutic approach in these patients are warranted.
RADT-10. DEVELOPMENT AND INTERNAL VALIDATION OF A PREDICTIVE SCORE FOR VERTEBRAL COMPRESSION FRACTURE AFTER STEREOTACTIC BODY RADIATION THERAPY FOR SPINAL METASTASES
Authors: Kowalchuk Roman , Johnson-Tesch Benjamin , Marion Joseph , Mullikin Trey , Harmsen William , Rose Peter , Siontis Brittany , Kim Dong Kun , Costello Brian , Morris Jonathan , Gao Robert , Shiraishi Satomi , Lucido John , Trifiletti Daniel , Olivier Kenneth , Owen Dawn , Stish Bradley , Waddle Mark , Laack Nadia , Park Sean , Brown Paul , Merrell Kenneth
Published: November 2021

PURPOSE

Vertebral compression fracture (VCF) is a potential adverse effect following stereotactic body radiation therapy (SBRT) for spinal metastases. In this analysis, we developed and internally validated a risk stratification model for VCF.

METHODS

From an initial set of 680 treatments, we excluded those with proton therapy, prior surgical intervention, or missing data. The final dataset had 464 treatments in 313 patients. Delineations of VCF and all radiographic components of the spinal instability neoplastic score (SINS) were determined by a radiologist. Recursive partitioning analysis (RPA) was conducted using separate training (70%), internal validation (15%), and test (15%) sets. The log-rank test was used as the criterion for node splitting.

RESULTS

With a median follow-up of 21 months, we identified 84 VCF (18%), including 65 (77%) de novo and 19 (23%) progressive fractures. There was a median 9 months (IQR: 3 – 21) to VCF. From an initial set of 15 candidate variables, six were identified using the backwards selection method, feature importance testing, and a correlation heatmap. Four were then selected in the highest-fidelity RPA models: epidural tumor extension, lumbar location, gross tumor volume > 10 cc, and SINS > 6. One point was assigned to each variable, and the resulting multivariate Cox model had a concordance of 0.760. Each one point increase in score was associated with increasing rates of VCF. Low-risk lesions (score: 0-1, n=273) had 2-year freedom from VCF of 92%, compared to 80% for intermediate-risk (score: 2, n=99) and 56% (score: 3-4, n=92) for high-risk lesions (p < 0.0001). Cumulative incidence curves with death as a competing risk showed increased VCF with higher scores via Gray’s test (p < 0.001).

CONCLUSIONS

Our internally-validated model identifies a subgroup of patients with high risk for VCF who may benefit from prophylactic surgical stabilization or vertebroplasty.
RADT-17. FOCUSED ULTRASOUND MEDIATED BLOOD–BRAIN BARRIER OPENING IS SAFE AND FEASIBLE CONCURRENT WITH AND ADJUVANT TO A CLINICAL RADIATION SCHEME FOR BRAINSTEM DMG
Authors: Tazhibi Masih , McQuillan Nicholas , Wei Hong-Jian , Pouliopoulos Antonios , Bendau Ethan , Englander Zachary , Webster Andrea , Yoh Nina , Zacharoulis Stergios , Konofagou Elisa , Wu Cheng-Chia
Published: November 2021

Diffuse midline gliomas (DMG) are pediatric tumors with dismal prognosis. When these tumors emerge in the brainstem, there exists no feasible method of surgical resection or systemic intervention, making ionizing radiation the sole therapeutic avenue to date. However, radiotherapy (RT) provides only marginal survival benefit as the topographically diffuse and highly infiltrative tumors spread in areas in which the blood-brain barrier (BBB) is relatively intact. Focused ultrasound (FUS) with intravenous microbubbles provides a compelling solution, transiently and non-invasively opening the BBB to allow drug delivery across the cerebrovasculature. Nonetheless, it remains unclear whether FUS can be safely administered at the brainstem in patients receiving RT. Therefore, the goal of this study was to assess the safety and feasibility of FUS administered concurrent with and adjuvant to a clinical hypofractionated radiation scheme for brainstem DMG. Non-tumor bearing B6 albino mice were randomly assorted into control, RT, FUS, and RT+FUS groups. Mice designated RT+FUS received 39Gy/13fx (hypofractionated RT scheme) to the brainstem with two sessions of FUS approximately 1 week apart. A single-element, spherical-segment FUS transducer driven by a function generator through a power amplifier was used with concomitant microbubble injection to sonicate the brainstem. Magnetic resonance imaging (MRI) was used to confirm BBB opening and cardiopulmonary measures were recorded throughout sonication. Vitals were assessed daily, and all treatment animals underwent Kondziela inverted screen testing and sequential weight lifting to assess brainstem-related strength and motor coordination deficits. In both FUS and RT+FUS mice, MRI confirmed brainstem BBB opening and subsequent closure within 96 hours. Mouse weights were stable, with slight drops (mean=5.5%) following FUS that resolved within three days. No attenuation in cardiorespiratory, strength, and motor coordination measurements was observed from FUS. FUS is a safe and feasible technique for brainstem BBB opening concurrent with and adjuvant to clinical hypofractionated RT.
RADT-19. CLINICAL OUTCOMES OF RADIATION THERAPY FOR BRAIN STEM GLIOMA
Authors: Pyone Khin , Myint Lay , Hnin Tint , Khaing Aye
Published: November 2021

PURPOSE/OBJECTIVES

Brain stem gliomas are up to 20% of all brain tumor in children and unusual in adults. Radiotherapy is mainstay of treatment. Surgery for brain stem glioma is difficult because of anatomical location. This study was performed to evaluate the clinical outcomes of radiotherapy in brain stem glioma.

METHODS

Retrospective analysis of brain stem glioma patients treated with radiation therapy (54Gy/30 fractions of IMRT/ 3D CRT) with or without surgery or chemotherapy or other agents.

RESULTS

Twenty-four patients (median age 11.8 years) were treated between 2016 and 2020. Male to female ratio was 2:3. Surgical approach (biopsy and partial removal) was done in 16 patients. Histology revealed that anaplastic ependymoma in 2 patients, low grade astrocytoma in 2 patients, anaplastic astrocytoma in 8 patients, glioblastoma in 4 patients and remaining 8 patients had no histologic diagnosis. Radiotherapy (dose- 54Gy/ 30 fractions) was given with the technique of IMRT or 3D CRT. At the time of follow up, 8 patients had local recurrence, 10 patients died of due to disease and recurrence, 14 patients were alive. Among alive patients, 2 patients were treated with chemotherapy and 12 patients with temozolomide for 12 cycles. Patients who received temozolomide got improvement in performance status and reduced clinical symptoms; among them, 6 patients had more than 50% objective tumor response in radiological findings for follow-up 3-6 months after radiotherapy. The 2-years overall survival (OS) rate was 58.3% and 2-years Event-free Survival (EFS) rate was 50%. The median survival time was 14 months. There is no grade 3 or greater acute and late toxicities.

CONCLUSION

As the LMIC country with limited resources, our results of radiotherapy followed by temozolomide in brain stem glioma have optimal outcomes. However, prospective studies of this select group of patients with larger number and longer follow up is required.
RADT-33. LONG-TERM OUTCOMES, TREATMENT UTILIZATION, AND PROGNOSTIC FACTORS FOR PEDIATRIC CHORDOMA: AN NCDB ANALYSIS
Authors: Cantrell James , Acharya Pawan , Vesely Sara , Confer Michael , Algan Ozer , Gunter Tyler
Published: November 2021

BACKGROUND

Chordomas are rare tumors arising from the embryonal notochord presenting at the base of skull, spine, or sacrum. Pediatric chordomas (PC) comprise less than 5% of all chordomas and are more likely to be atypical or dedifferentiated. Evidence for management is limited to single institution series with 5-year overall survival (OS) between 60-100%.

METHODS

Using the NCDB Participant User File, a retrospective observational cohort study was performed. The cohort was defined using the bone-soft-tissue, brain, and central nervous system databases selecting for cases with chordoma ICD-03 codes and age ≤ 25 years. Kaplan Meier method, log-rank test, and Cox proportional hazards regression were performed.

RESULTS

297 patients from 2004-2017 met inclusion criteria for descriptive analysis with 269 cases included for survival analysis. Mean age was 16.9 years, with 10% less than age 5. The cohort was 55% female, 8% Black, and 79% White. Primary sites included bones of the skull (70%), spine (22%), and pelvis (6%). Regarding treatment, 7% had no resection, 49% sub-total resection (STR), 33% gross-total resection (GTR), and 11% unspecified resection. 51% received radiation therapy with 46% of those receiving proton therapy. 7% received chemotherapy. The 1, 3, 5, and 10-year OS was 95%, 86%, 77%, and 72%. Selected prognostic factors from univariable OS model for OS analysis included: age > 5 (HR 0.30 (95% CI 0.16-0.57) p = 0.0002), surgical resection [GTR (HR 0.28 (95% CI 0.12-0.63) p = 0.0023) and STR (HR 0.27 (95% CI 0.12-0.59) p = 0.0011)], and radiation dose ≥ 7200cGy (HR 0.40 (95% CI 0.16-0.99) p = 0.047).

CONCLUSION

In the largest cohort reported for PC, 3 and 10-year OS was 86% and 72%. Age, surgery, and radiation dose are important prognostic factors. Propensity score analysis to gauge effect of treatment, tumor, and patient characteristics on OS is forthcoming.
CTIM-09. PHASE I STUDY OF PD-L1 INHIBITION WITH AVELUMAB AND LASER INTERSTITIAL THERMAL THERAPY IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Hormigo Adilia , Chiu Daniel , Hahn Mary , Qi Jingjing , Lee Brian , Mandeli John , Ghatan Saadi , Hadjipanayis Constantinos , Yong Raymund , Germano Isabelle , Gnjatic Sacha , Kim-Schulze Seunghee
Published: November 2021

BACKGROUND

The treatment of glioblastoma (GBM) poses many challenges. The use of immune checkpoint inhibition (ICI) has been disappointing as GBM is characterized by a low mutational burden and low infiltration by T cells. The combination of ICI with other treatment modalities may improve efficacy.

METHODS

Patients with recurrent GBM were treated with 800 mg avelumab, a human IgG1 antibody directed against PD-L1, either alone (in part A) or within a week after MRI-guided laser interstitial thermal therapy (LITT, in part B) and by-weekly thereafter (NCT03341806). To spare steroid use, bevacizumab was allowed to be combined with avelumab. The primary objective was to characterize the tolerability and safety of the regimen. The secondary objectives included overall survival, progression-free survival, and signature of plasma analytes.

RESULTS

A total of 12 patients (median age 64, range 37 - 73) enrolled from June 2018 to November 2019, 5 in part A and 7 in part B. Three serious adverse events (SAE) occurred in the same patient, not leading to death. There were 94 AEs reported, 5 grade 3, 28 grade 2, and 61 grade 1. The median PFS was 16.7 weeks (range 7.4-56.7) for patients in Part A and 30.9 weeks (range 8.5-77.7) for patients in Part B. The median survival for patients in part A was 11 months and 13.5 months for part B. The risk ratio of death by combining bevacizumab was 0.573 (p=0.258) with significantly decreased levels of peripheral blood plasma inflammatory markers such as EGF, CXCL5, VEGFA, LAP.TGβ1, ANGPT2 in women.

CONCLUSIONS

Avelumab was generally well-tolerated, and the combination with LITT had a manageable safety profile and increased survival in a subset of patients. The addition of bevacizumab may increase survival by lowering cytokine expression in a gender-dependent manner. These results warrant further investigation in the next phase study.
CTIM-17. INTRA-CRANIAL ADMINISTRATION OF CTLA-4 AND PD-1 IMMUNE CHECKPOINT-INHIBITING MONOCLONAL ANTIBODIES IN RECURRENT GLIOBLASTOMA PATIENTS: A MULTI-COHORT ADAPTIVE PHASE I CLINICAL TRIAL
Authors: Duerinck Johnny , Geens Wietse , Schwarze Julia Katharina , Bertels Cleo , Tijtgat Jens , Awada Gil , Vaeyens Freya , cras Louise , Nijland Lynn , Vanbinst Anne-Marie , Everaert Hendrik , Michotte Alex , Janssens Toon , Caljon Ben , Cauwenbergh Tom , Bruneau Michaël , Forsyth Ramses , Tuyaerts Sandra , Neyns Bart
Published: November 2021

BACKGROUND: Intracerebral (iCE) administration of nivolumab (NIVO) and ipilimumab (IPI) after resection of recurrent glioblastoma (rGB), followed by repeated intravenous(IV) NIVO was recently shown to be feasible, safe and associated with encouraging survival. Subsequent cohorts were defined to investigate the addition of biweekly intracavitary (iCA) or intrathecal (iTH) NIVO +/- IPI administrations. METHODS Four groups were defined according to rGB resectability and postoperative treatment schedule. Group A and D underwent biopsy, B and C maximal safe resection. All patients received iCE injections of 10 mg/1ml NIVO + 5 mg/1ml IPI at the end of surgery, after which an Ommaya catheter was implanted iCA (A, B and C) or iTH (D). Following surgery, all patients received biweekly IV low-dose NIVO(10mg) combined with iCA/iTH 10 mg NIVO (A and B) + 1, 5 or 10 mg IPI (C and D) for up to 24 weeks. NIVO/IPI concentrations were dosed in the cerebrospinal fluid (CSF). Gene sequencing and RNA gene expression profiling were performed on all tissue samples RESULTS 39pts(27 male; 16 in A, 16 in B, 4 in C, 3 in D; recruitment ongoing in C+D) were enrolled. All patients received the predefined dose of iCE IPI/NIVO. Most frequent AEs were fatigue (n=30), headache (n=19), confusion (n=14), dysphasia (n=13), and fever (n=10). Ommaya infection occurred in 5patients, subacute neurological deterioration requiring corticosteroids in 6patients. There were no G5 AEs. irAEs were infrequent and mild. Median PFS and OS were 5w(95% CI 1-8) and 23w(95% CI 0-53) in A and 13w(95% CI 7-19) and 42w(95% CI 30-54) in B, respectively. >90% of CSF samples had elevated protein levels and lymphocytic pleocytosis. There was no evidence for accumulation of NIVO/IPI in the CSF. CONCLUSION Repeated intracavitary or intrathecal administration of NIVO +/- IPI in rGB is feasible and safe. Favourable survival outcome is seen in patients amenable to surgical resection.
CTIM-20. FINAL RESULTS OF CONTROLLED IL-12 MONOTHERAPY AND IN COMBINATION WITH PD-1 INHIBITOR IN ADULT SUBJECTS WITH RECURRENT GLIOBLASTOMA
Authors: Lukas Rimas , Oberheim-Bush Nancy Ann , Cavaliere Robert , Landolfi Joseph , Yu John S , Chen Clark , Cordova Christine , Amidei Christina , Buck Jill Y , Hadar Nira , Demars Nate , Miao John , Loewy John , Estupinan Taylor , Chadha Kamal , Cooper Laurence J N , Chiocca E Antonio
Published: November 2021

Ad-RTS-hIL-12(Ad) is a gene therapy candidate conditionally expressing IL-12 under the transcriptional control of veledimex(V) acting via the RheoSwitch Therapeutic System® gene switch. Veledimex plasma and tumor PK demonstrated a dose-response relationship and crossing the BBB. PD-1+ T-cells were increased in tumor biopsy samples after treatment with Controlled-IL-12 in a phase-l study. This finding was the rationale for conducting 2 trials of Controlled-IL-12 in combination with PD-1-inhibitor to enhance T-cell-mediated anti-tumor effects. Data from two completed phase-I studies (presented in SNO2020), and an ongoing phase-II study of Controlled-IL-12 with cemiplimab study for the treatment of recurrent glioblastoma (rGBM) will be discussed. Ziopharm has conducted 3 phase-I (NCT02026271/NCT03679754 (monotherapy), NCT03636477 (combination with nivolumab)) and one phase-ll (NCT04006119) multicenter, open-label, single-arm trial in subjects with rGBM is evaluating Ad (single intratumoral injection, 2 x 1011-viral-particles, Day0) with oral V dosing (20mg, Days 0-14) with cemiplimab infusions (350 mg IV) on Days -7, 15, then Q3W. Systemic biomarkers (serum cytokines, and immune-activation-markers), local effects (tumor cytokines, T-cell immunobiology, pathology), neoepitope, and imaging will be assessed. Subject characteristics (Controlled IL-12 monotherapy (n=75); combination (Controlled IL-12 with anti-PD-1s) (n=61) were consistent across all 3 studies. Safety profiles were comparable between monotherapy and in combination with anti-PD-1s. Adverse reactions (ARs) after nivolumab or cemiplimab were consistent with labeling of anti-PD-1s. ARs related to Controlled IL-12 were all manageable and reversible with no synergistic toxicities in combination with anti-PD-1s. Increases in serum cytokine levels and pathology findings consistent with immune-mediated anti-tumor effect were observed in subjects who received Controlled-IL-12 monotherapy and in combination with anti-PD-1s. Final survival data and results from neoepitope analysis will be presented. Further investigation is warranted to understand the impact of monotherapy vs. combination, concurrent steroids use and unifocal vs. multifocal disease on overall survival in subjects with rGBM receiving Controlled-IL-12.
CTIM-33. PHASE II TRIAL OF VACCINE IMMUNOTHERAPY IN PRIMARY GLIOBLASTOMA: ADJUNCTIVE AUTOLOGOUS DENDRITIC CELLS PULSED WITH LYSATE FROM IRRADIATED SELF-RENEWING AUTOLOGOUS TUMOR CELLS (AV-GBM-1)
Authors: Bota Daniela A , Piccioni David E , Duma Christopher M , LaRocca Renato V , Kesari Santosh , Abedi Mehrdad , Carrillo Jose A , Aiken Robert D , Hsu Frank , Kong Xiao-Tang , Taylor Thomas H , Hsieh Candace , Nistor Gabriel , Dillman Robert
Published: November 2021

In primary glioblastoma (GBM), overall survival (OS) is poor despite standard aggressive therapy. Adjunctive AV-GBM-1 vaccine immunotherapy may improve OS. In this multi-institutional phase II trial, key eligibility criteria for intent-to-treat (ITT) enrollment were: (1) primary GBM, (2) age < 70 years when GBM was resected, (3) successful GBM cell culture, (4) successful monocyte collection by leukapheresis, (5) KPS > 70 post-surgery, and (6) plan to treat with concurrent RT/TMZ. Dendritic cells (DC) were differentiated from monocytes by culturing in IL-4 and granulocyte-macrophage colony stimulating factor (GM-CSF). AV-GBM-1 consisted of autologous DC incubated with autologous tumor antigens contained in the lysate of irradiated cultured GBM cells. After recovery from RT/TMZ, doses were admixed with 500 mcg GM-CSF; up to 8 doses were injected subcutaneously over 6 months. Patients were not excluded by apparent progression or pseudo-progression post RT/TMZ. OS and progression-free-survival (PFS) were calculated from ITT enrollment. The success rate was 97% for both GBM cell cultures and collection of monocytes; 60/60 vaccines were successfully manufactured. Median age was 59 years. 57 patients received 392 injections. After two weekly injections there were significant increases in plasma lipocalin-2 and angiopoietin-1, and decreases in thrombospondin-5, angiotensinogen, and beta-fibroblast growth factor. The most common adverse events attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). With follow up from 15.2 to 32 months, median PFS and OS were 10.3 (8.5,11.6 95% CI) and 16.0 (13.0,21.3 95% CI) months respectively. OS was better in the 25 patients who had methylguanine-methyltransferase (MGMT) methylation and/or isocitrate dehydrogenase (IDH) mutation. Age was not independently correlated with survival. From date of first injection, OS was not increased in 14 patients who were treated with alternating electrical tumor-treating fields. CONCLUSION: feasibility, safety, and PFS were encouraging. A phase III trial is in development.

Clinicaltrials.gov NCT03400917.
CTNI-08. DB102-01 ENGAGE STUDY: A BIOMARKER-GUIDED, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTI-CENTER PHASE 3 CLINICAL TRIAL OF DB102 IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM)
Authors: Bota Daniela , Butowski Nicholas , Piccioni David , De la Fuente Macarena , Mao Ying , Li Wen-Bin , Trusheim John , Fink Karen , Campian Jian , Lobbous Mina , Portnow Jana , Zhu Jay-Jiguang , Pearlman Michael , Rudnick Jeremy , Lesser Glen , Drappatz Jan , Vaillant Brian , Sun Show-Li , Luo Wen
Published: November 2021

Precision medicine is vital for treating many cancers. Lack of valid biomarkers might contribute to the failure of drug therapy for GBM. The Denovo Genomic Marker 1 (DGM1), a novel pharmacogenomic biomarker, has been discovered by a genome-wide screen of patients treated with DB102 (enzastaurin) in a trial for lymphoma. Similarly, retrospective analyses showed that DB102 significantly improved outcomes in the biomarker positive GBM patients treated with DB102, regardless of MGMT promoter methylation status. The ENGAGE Study (DB102-01, NCT03776071) is a global Phase 3 clinical trial to confirm clinical benefits in patients with newly diagnosed GBM who are DGM1 biomarker positive. This is a prospective, randomized, double-blind, placebo-controlled, multi-center study. A total of 318 patients with newly diagnosed GBM will be enrolled. After screening, patients will be randomized to receive radiation therapy (RT) and temozolomide (TMZ) plus either DB102 or a matched placebo for 6 weeks in the Concurrent Phase, followed by DB102 or placebo for approximately 5 weeks in the Single-Agent Phase and then TMZ plus DB102 or placebo in the Adjuvant Phase (up to 12 cycles). Thereafter DB102 or placebo may be continued as a single agent for up to 2 years. The primary endpoint is overall survival (OS). The secondary endpoints include progression free survival (PFS), objective response rate (ORR) and drug safety. By April 2021, the safety-run-in part was completed. The study is now open for enrollment in the US and soon in Canada and China.
CTNI-11. TUMOR-TREATING FIELDS COMBINED WITH SECOND-LINE CHEMOTHERAPY IN RECURRENT GLIOBLASTOMA: A MATCHED RETROSPECTIVE STUDY
Authors: Mou Yonggao , Qun-ying Yang , Guo Cheng-Cheng , Deng Meiling , Chen Yin-Sheng , Du Xiao-Jing , Wu Shao-xiong , Wang Jian , Ke Sai
Published: November 2021

OBJECTIVE

Tumor-treating Fields (TTFields) has been approved for patients with newly diagnosed and recurrent GBM. However, TTFields combined with second-line chemotherapy has not been well studied in china. This study aims to explore the efficacy and safety of such combination therapy for recurrent GBM.

METHODS

Forty-nine patients with supratentorial GBM who failed the standard Stupp treatment from April 2019 to January 2021 in our center were enrolled. Fourteen patients received combination therapy while 35 received second-line chemotherapy alone (temozolomide or CPT-11) as a control. PFS, OS, and adverse reactions were compared.

RESULTS

There were no significant differences between these two groups in baseline characteristics except the use of anti-angiogenesis drugs which was higher in the control group. The median duration of TTFields was 19 weeks (10.1-43.4) with a median compliance rate of 93.5% (67-97%). The control group had a higher rate of disease progression than the combination group (adjusted HR=2.49, 95% CI: 1.08-5.75, P=0.033). The 6-month PFS rate was 55.6% (95% CI: 26.6%-77.0%) in the combination group, and 29.2% (95% CI：14.9%-45.1%) in the control group (p=0.03). The median OS was 8.6 months (95% CI: 3.9-NE) and 7.1 months (95% CI:5.1-9.8), respectively (HR=1.29, P= 0.56). Skin rash beneath the tranducer arrays was a common adverse event in the combination group (42.6% mild and 14.3% moderate). This condition was easily treated with topical corticosteroids and did not require substantial treatment breaks.

CONCLUSION

TTFields combined with second-line chemotherapy had significantly less progression rate than chemotherapy alone for patients with recurrent GBM. In addition, the combination therapy was well tolerated.
CTNI-18. PHASE I AND PRELIMINARY PHASE 0 RESULTS OF ABTC 1801: A MULTI-ARM CLINICAL TRIAL OF THE PARP INHIBITOR PAMIPARIB (BGB290) WITH VERY LOW DOSE METRONOMIC TEMOZOLOMIDE IN RECURRENT IDH MUTANT GLIOMAS
Authors: Schiff David , Bindra Ranjit , Li Jing , Ye Xiaobu , Ellingson Benjamin , Walbert Tobias , Campian Jian , Nabors L Burt , Lieberman Frank , Ozer Byran , Desai Arati , Omuro Antonio , Wen Patrick , Desideri Serena , Fisher Joy , Grossman Stuart
Published: November 2021

BACKGROUND

Preclinical studies have demonstrated that IDH1-mutant (IDHmt) gliomas harbor a BRCAness phenotype with a defect in homologous recombination that confers PARP inhibitor sensitivity. Pamiparib (BeiGene BGB-290) is an effective PARP-trapping PARP inhibitor with demonstrated favorable brain penetration in animal models.

METHODS

ABTC 1801 is a study examining the safety, pharmacokinetics, and efficacy of the combination of pamiparib with low dose metronomic temozolomide in recurrent IDHmt gliomas. The Phase I component utilized a 3 + 3 design with a target DLT rate ≤ 33%. Pamiparib dose was 60 mg BID and temozolomide dose 20 mg daily, with dose de-escalation levels for anticipated hematological toxicity.

RESULTS

Seven patients were enrolled on the Phase I portion at dose level 1; one patient was replaced for inadequate dosing secondary to non-compliance. All patients had prior radiotherapy and temozolomide; 4/7 had received multiple lines of alkylator therapy including nitrosoureas. Median age was 45, KPS 90, and number of prior relapses 3. Four patients had anaplastic astrocytoma, 2 anaplastic oligodendroglioma, and 1 glioblastoma. One of 6 patients (16.7%) experienced DLT during the first cycle (grade 3 neutropenia and thrombocytopenia). Two additional patients had grade 2 neutropenia. Two patients remain on study treatment at 12+ and 10+ months, while a third progressed at 10.1 months (PFS-6 43%). Tumor tissue was collected from two patients in the surgical arm. In enhancing and non-enhancing tumors, the mean unbound pamiparib concentrations were 198 and 160 nmol/L (or nmol/kg), respectively, which were > 20-fold the in vitro IC50 for PARP inhibition; mean unbound tumor-to-plasma ratios were 0.65 and 0.38.

CONCLUSIONS

Phase I results support pamiparib 60 mg BID with temozolomide 20 mg daily as the dosages for the Phase II study. Preliminary Phase 0 data suggest that pamiparib likely achieves sufficient pharmacologically active concentrations in both enhancing and non-enhancing brain tumors.
CTNI-22. A PHASE 0/1 ‘TRIGGER’ TRIAL OF RIBOCICLIB PLUS EVEROLIMUS IN RECURRENT HIGH-GRADE GLIOMA
Authors: Sanai Nader , Tien An-Chi , Jiang Jun , Chang Yu-Wei , Pennington-Krygier Chelsea , DeSantis Anita , Fujita Yoko , Kim Seongho , Li Jing , Mehta Shwetal
Published: November 2021

BACKGROUND

mTOR activation is a mechanism of resistance in CDK4/6 targeting. We evaluated tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of combined CDK4/6 and mTOR inhibition in recurrent high-grade glioma (HGG) patients.

METHODS

Recurrent HGG patients with (1) intact RB, (2) CDKN2A/B deletion or CDK4/6 amplification, and (3) PTEN loss or PIK3CA mutations receive five days of presurgical ribociclib plus everolimus prior to resection at 2, 8 or 24 hours after the final dose. Beginning at 400mg QD ribociclib plus 2.5mg QD everolimus, six dose-escalations summit at 600mg QD plus 60mg QW. Gadolinium [Gd]-enhancing and nonenhancing tumor regions, CSF, and plasma are collected. Total and unbound drug concentrations are determined using validated LC-MS/MS methods. RB and S6 phosphorylation are compared to matched archival tissue. To select patients for a therapeutic expansion phase of combined drug therapy, the protocol includes a PK ‘trigger’ (i.e., for each drug, unbound concentration in Gd-nonenhancing tumor > 5-fold biochemical IC50) and a PD ‘trigger’ (i.e., for each tumor, > 30% decrease in pRB and pS6).

RESULTS

21 patients with WHO Grade III (n=2) and IV (n=19) gliomas were enrolled into the Phase 0 component of the study. No dose-limiting toxicities were observed. In Gd-nonenhancing tumor regions, the median unbound concentration of ribociclib was 719 nM, whereas unbound everolimus tumor concentrations were undetectable. Across all dose-levels, 62% (13/21) and 22% (5/21) of tumors demonstrated decreased tumor RB and S6 phosphorylation, respectively. Tumor proliferation (MIB-1) was decreased in 67% (14/21) of all patients. No patients qualified for the therapeutic expansion phase.

CONCLUSION

In adult HGG, ribociclib achieves pharmacologically-relevant concentrations in Gd-nonenhancing tumor whereas everolimus exhibits no meaningful tumor penetration. These findings support further clinical development of ribociclib, but not everolimus, for the treatment of high-grade glioma patients.
CTNI-25. CASE STUDY OF AN EXCEPTIONAL RESPONDER: ENZASTAURIN LONG TERM EFFICACY IN A PATIENT WITH PRIMARY AND RECURRENT GLIOBLASTOMA MULTIFORME (GBM)
Authors: Clarke Jennifer
Published: November 2021

Enzastaurin (ENZA, DB102) is an oral serine/threonine kinase inhibitor targeting the protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K)/AKT pathways to inhibit tumor cell proliferation, induce tumor cell apoptosis, and suppress tumor-induced angiogenesis. We report the long-term clinical response of a GBM patient treated with ENZA who has survived for 15 years from initial diagnosis, despite tumor recurrence 5 years ago. In 2006, the 44-year-old man was diagnosed with GBM and underwent surgical resection of the tumor. He subsequently enrolled in a Phase I/II trial evaluating ENZA in newly diagnosed GBM and gliosarcoma (NCT00402116), in September 2006. He was treated with radiation and concurrent temozolomide (TMZ) + ENZA, followed by adjuvant TMZ + ENZA, which he tolerated well. He stopped treatment electively in November 2010, after 51 adjuvant cycles, in the setting of stable imaging without evidence of tumor activity. The patient did well until January 2016, when a serial MRI scan showed tumor progression; he underwent a second surgical resection (pathology: recurrent GBM, IDH1 R132H neg, ATRX retained, EGFR amplified, MGMT methylated) followed by re-irradiation with concurrent TMZ. Given the patient’s prior prolonged disease control, he started a compassionate treatment of ENZA in combination with adjuvant TMZ in April 2016. TMZ was stopped in June 2018 after 28 cycles; he continues single agent ENZA to date, with no evidence of tumor progression as of May 2021. Consistent with DGM1 (Denovo Genomic Marker 1) being an ENZA efficacy predicting biomarker, the patient is DGM1 positive. This case provides clinical evidence that the addition of ENZA to standard of care may provide substantial long-term benefit in DGM1 positive patients with GBM. A Phase 3 study of ENZA in DGM1 positive newly diagnosed GBM patients is currently ongoing (ENGAGE study, NCT03776071).
CTNI-29. SAFETY AND FEASIBILITY OF RHENIUM-186 NANOLIPOSOME (186RNL) IN RECURRENT GLIOMA: THE RESPECT™ PHASE 1 TRIAL
Authors: Brenner Andrew , Bao Ande , Phillips William , Awasthi Vibhudutta , Patel Toral , Weinberg Jeffrey , Floyd John
Published: November 2021

BACKGROUND

Liposomal rhenium-186 (186RNL) is a potent source of beta particles with short path length, variable dose rate, high radiation density and gamma emission. Preclinically, 186RNL delivered via convection enhanced delivery (CED) achieves very high doses of targeted radiation with a wide therapeutic index. We report the results of ReSPECT, the first in man, dose escalation phase 1 trial of 186RNL in recurrent glioma.

METHODS

Following computer assisted treatment planning and placement of intracranial catheter(s), we performed a single administration of 186RNL by CED. We obtained whole body planar and SPECT/CT imaging on days 1-8 following treatment for dosimetry and distribution and followed patients for safety, progression and survival.

RESULTS

Twenty-one patients across 7 cohorts received 1.0-22.3mCi in a volume of 0.6-8.80mL. Mean tumor volume was 8.3mL (0.9-22.8mL). Patients had a mean of 1.7 recurrences, 5 received prior bevacizumab. Overall, 19/21 patients and all after cohort 4 had grade 4 glioma (glioblastoma). We used a CED rate of 5-20µl/min per catheter, with 1-4 catheters used per patient. Mean absorbed radiation dose to the tumor was 255Gy (8.9-740Gy) while exposure outside the brain was negligible. The mean percentage tumor in the treated volume (Tu/Tv) was 60.3% (19.8%-100%). Thus far, we have observed no dose limiting toxicities, one grade 3 treatment related adverse event (AEs), and the majority of AEs were mild in intensity. The incidence and severity of AEs did not correlate with increasing dose. Mean Tu/Tv in patients not receiving prior bevacizumab was 75% vs. 48% in those that had. Thus far, overall survival (OS) in 16 bevacizumab naïve patients is 49 weeks with 7 (44%) patients still alive and a positive correlation of OS to Tu/Tv.

CONCLUSIONS

186RNL achieves high absorbed doses without significant toxicity with favorable overall survival.