Progressive High-grade Glioma Research Articles

A review of current therapeutics targeting the mitochondrial protease ClpP in diffuse midline glioma, H3 K27-altered.

Diffuse midline gliomas (DMGs) are devastating pediatric brain tumors recognized as the leading cause of cancer-related death in children. DMGs are high-grade gliomas (HGGs) diagnosed along the brain's midline. Euchromatin is the hallmark feature of DMG, caused by global hypomethylation of H3K27 either through point mutations in histone H3 genes (H3K27M), or by overexpression of the enhancer of zeste homolog inhibitory protein. In a clinical trial for adults with progressive HGGs, a 22-year-old patient with a thalamic DMG, H3 K27-altered, showed a remarkable clinical and radiological response to dordaviprone (ONC201). This response in an H3 K27-altered HGG patient, coupled with the lack of response of patients harboring wildtype-H3 tumors, has increased the clinical interest in dordaviprone for the treatment of DMG. Additional reports of clinical benefit have emerged, but research defining mechanisms of action (MOA) fall behind dordaviprone's clinical use, with biomarkers of response unresolved. Here, we summarize dordaviprone's safety, interrogate its preclinical MOA identifying the mitochondrial protease "ClpP" as a biomarker of response, and discuss other ClpP agonists, expanding the arsenal of potential weapons in the fight against DMG. Finally, we discuss combination strategies including ClpP agonists, and their immunomodulatory effects suggestive of a role for the tumor microenvironment in DMG patient response.

Imaging-Based Patterns of Failure following Re-Irradiation for Recurrent/Progressive High-Grade Glioma.

Re-irradiation (ReRT) is an effective treatment modality in appropriately selected patients with recurrent/progressive high-grade glioma (HGG). The literature is limited regarding recurrence patterns following ReRT, which was investigated in the current study. Patients with available radiation (RT) contours, dosimetry, and imaging-based evidence of recurrence were included in the retrospective study. All patients were treated with fractionated focal conformal RT. Recurrence was detected on imaging with magnetic resonance imaging (MRI) and/ or amino-acid positron emission tomography (PET), which was co-registered with the RT planning dataset. Failure patterns were classified as central, marginal, and distant if >80%, 20-80%, or <20% of the recurrence volumes were within 95% isodose lines, respectively. Thirty-seven patients were included in the current analysis. A total of 92% of patients had undergone surgery before ReRT, and 84% received chemotherapy. The median time to recurrence was 9 months. Central, marginal, and distant failures were seen in 27 (73%), 4 (11%), and 6 (16%) patients, respectively. None of the patient-, disease-, or treatment-related factors were significantly different across different recurrence patterns. Failures are seen predominantly within the high-dose region following ReRT in recurrent/ progressive HGG.

Acetazolamide versus placebo for cerebral oedema requiring dexamethasone in recurrent and/or progressive high-grade glioma: phase II randomised placebo-controlled double-blind study

ObjectivesSymptoms of raised intracranial pressure (ICP) in recurrent high-grade glioma (HGG) generally require corticosteroid treatment, often causing toxicity with variable effects on ICP symptoms. Acetazolamide reduces ICP when used in...

EXTH-60. ONCR-GBM, A NOVEL ARMED ONCOLYTIC HSV-1 VECTOR ENGINEERED FOR EFFICACY AND SAFETY IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is the most common type of primary brain tumor in adults, with a 5-year overall survival of only 7%. Oncolytic viruses are a promising and active area of research in GBM with the recent approval of an oncolytic HSV-1 vector, teserpaturev (Delytact, also known as G47Δ, Daiichi Sankyo) for recurrent GBM based on an overall survival of 92% at 1 year. G207, an HSV-1 vector more attenuated than teserpaturev, recently reported acceptable tolerability with evidence of responses in children with recurrent or progressive high-grade glioma. These vectors are not expressing any cDNA transgene that may enhance and prolong antitumor activity. We report here the development of ONCR-GBM, an oncolytic HSV-1 vector specifically engineered for safety using a microRNA attenuation strategy to limit viral replication in healthy cell type of the CNS. ONCR-GBM has been developed from a novel potently oncolytic strain of HSV-1 and optimized for infection of GBM tumor cells. Antitumor efficacy has been further enhanced through the expression of multiple payloads designed to modify the immunosuppressive tumor microenvironment of GBM. We previously reported that a vector expressing IL-12 and a PD-1 antagonist nanobody achieved &amp;gt; 90% survival after a single injection in the GL261-Nectin1 orthotopic model. This vector promoted immune cell recruitment and activation in tumors and protected surviving animals from a subsequent tumor rechallenge. Additional payloads selected for interfering with the immune suppressive stroma in GBM have been evaluated for potentiating the response of IL-12 and anti PD-1 expressing HSV-1. We will present the outcome of the in vivo screen, and the selection of the optimal combination of payloads featured in ONCR-GBM clinical candidate.

Patterns of Failure Following Stereotactic Radiosurgery Salvage for Recurrent High-Grade Glioma

<h3>Purpose/Objective(s)</h3> Stereotactic radiosurgery (SRS) is an increasingly used treatment for patients with progressive high-grade glioma (HGG). We sought to determine which demographic and clinical factors are associated with pattern of recurrence and outcome following SRS to better predict which patients would benefit from local salvage. <h3>Materials/Methods</h3> This retrospective analysis of a prospectively maintained database included continuous patients treated with SRS salvage at a single institution between January 2008 and May 2020. Patterns of failure were classified according to the distance from the prescription isodose line. Local failures included in-field (within the prescription isodose line), marginal (< 2 cm), and regional (2-5 cm). Distant failures were > 5 cm. Survival was estimated using Kaplan-Meier methods. The Wilcoxon rank-sum test, Kruskal-Wallis test, and Spearman correlations were used to examine associations between patterns of failure and demographic and clinical variables at first failure. Multilevel mixed-effects parametric regressions were used to identify predictors of SRS failure. <h3>Results</h3> One hundred forty-eight patients (males, 56.8%; non-Hispanic White, 72.3%) ages 20 to 83 years (median, 58 years) with HGG (WHO Grade IV, 92.6%) underwent salvage to a total of 412 targets. The median (interquartile range) size of target was 3.4 (1.0-8.7) cm³. The median dose was 18 (16-20) Gy. The median time from diagnosis to salvage was 12.1 (7.6-19.3) months. With a median follow up of 8.2 months, 62 (41.9%) patients developed progression following SRS. Progression-free survival at 6 and 12 months were 64.4% (95% confidence interval [CI]: 55.7-71.7) and 36.8% (95% CI: 28.7-45.0), respectively. Fifty (80.7%) patients developed local, two (3.2%) distant, and 10 (16.1%) concomitant local and distant failure. Actuarial local control at 6 and 12 months were 80.8% (95% CI: 72.4-86.8) and 61.8% (95% CI: 51.4-70.7), respectively. Of 60 local failures, 31 (51.7%) were in-field, 25 (41.7%) marginal, and four (6.7%) regional. Median overall survival was 26.6 months from diagnosis and 13.0 months from first GK treatment. Non-White race (HR = 0.32, 95% CI: 0.15-0.66) and GK dose (HR = 0.87, 95% CI: 0.79-0.95, P = 0.002) were independent predictors of SRS failure. Non-White race (r_s = .31, P = 0.012) and GK target size (X² (3, N = 62) = 10.09, P = 0.017) were positively associated with a more distant pattern of failure. Age at diagnosis, sex, and glioma grade were not associated (P > 0.05) with GK failure or pattern of failure. No Grade 4 or 5 toxicity was observed. <h3>Conclusion</h3> SRS salvage is a safe and effective treatment for select patients with progressive HGG. The dominant pattern of failure following salvage was local; approximately half of local progressions were in-field. Higher dose decreased the hazard for progression, indicating that some patients may benefit from dose escalation.

Postmortem study of organ-specific toxicity in glioblastoma patients treated with a combination of temozolomide, irinotecan and bevacizumab.

Systemic chemotherapy includingmonotherapy with temozolomide (TMZ) or bevacizumab (BEV); two-drug combinations, such as irinotecan (IRI) and BEV, TMZ and BEV and a three-drug combination with TMZ, IRI and BEV (TIB) have been used in treating patients with progressive high-grade gliomas including glioblastoma (GBM). Most patients tolerated these regimens well with known side effects of hypertension, proteinuria, and reversible clinical myelosuppression (CM). However, organ- or system- specific toxicities from chemotherapy agents have never been examined by postmortem study. This is the largest cohort used to address this issue in glioma patients. Postmortem tissues (from all major systems and organs) were prospectively collected and examined by standard institution autopsyand neuropathologicalproceduresfrom 76 subjects, including gliomas (N = 68, 44/M, and 24/F) and brain metastases (N = 8, 5/M, and 3/F) between 2009 and 2019. Standard hematoxylin and eosin(H&E) were performed on all major organs including brain specimens.Electronic microscopic(EM) study was carried out on 14 selected subject's kidney samples per standard EM protocol. Medical records were reviewed with adverse events (AEs) analyzed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. A swimmer plot was utilized to visualize the timelines of patient history by treatment group. The binary logistic regression models were performed to explore any associations between treatment strategies and incident myelosuppression. Twenty-four glioma subjects were treated with TIB [median: 5.5 (range: 1-25) cycles] at tumor recurrence.Exposure to IRI significantly increased the frequency of CM (p = 0.05). No unexpected adverse events clinically, or permanent end-organ damage during postmortem examination was identified in gliomasubjects who had received standard or prolonged duration of BEV, TMZ or TIB regimen-based chemotherapies except rare events of bone marrow suppression.The most common causes of death (COD) were tumor progression (63.2%, N = 43) followed by aspiration pneumonia (48.5%, N = 33) in glioma subjects. No COD was attributed to acute toxicity from TIB. The study also demonstrated that postmortem kidney specimen is unsuitable for studying renal ultrastructural pathological changes due to autolysis. There is no organ or system toxicity by postmortem examinations among glioma subjects who received BEV, TMZ or TIB regimen-based chemotherapies regardless of durations except for occasional bone marrow suppression and reversible myelosuppression clinically.IRI, but not the extended use of TMZ, significantly increased CM in recurrent glioma patients. COD most commonly resulted from glioma tumor progression with infiltration to brain stem and aspiration pneumonia.

CTIM-05. A PHASE 1/2 STUDY OF THE COMBINATION OF INDOXIMOD AND TEMOZOLOMIDE FOR ADULT PATIENTS WITH TEMOZOLOMIDE-REFRACTORY PRIMARY HIGH-GRADE GLIOMAS

Abstract BACKGROUND Optimal management of progressive high-grade gliomas (HGG) is not fully defined and outcomes are poor. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme which converts tryptophan to kynurenines, which contribute to the immunosuppresive tumor microenvironment (TME). Targeting the TME by inhibiting IDO1 is a strategy for potential improvement in survival in HGG. METHODS A phase 1/2 trial using the IDO1 inhibitor indoximod was conducted in progressive grade 3 and 4 gliomas. The phase 1 cmponent used a 3 + 3 design escalating indoximod from 600mg po BID to 1200mg po BID in conjunction with temozolomide (150 mg/m2, 5/28 days). The phase 2 component consisted of 3 cohorts: A) indoximod+temozolomide B) indoximod+temozolomide+bevacizumab (patients already on bevacizumab) C) indoximod+temozolomide+stereotactic radiosurgery (SRS). Patients were treated until progression or toxicity. RESULTS 33.3% of patients developed indoximod TEAEs. There were no dose limiting toxicities in the phase 1 component (n=12). 1200 mg BID was established as the phase 2 dose of indoximod. In the phase 2 component (n=148) PFS6 was 74% (A), 93% (B), 70% (C). Median OS was 289 days [10.3 months](A), 159 days [5.7 months](B), 285 days [10.2 months](C). Correlative study results will be available for meeting presentation. CONCLUSIONS The IDO1 inhibitor indoximod proved safe and tolerable in conjunction with temozolomide, bevacizumab, and SRS in patients with progressive HGG. There was a trend toward better survival outcomes when indoximod was combined with temozolomide alone or temozolomide+SRS.

18F-DOPA-PET-Guided Re-Irradiation for Recurrent High-Grade Glioma: Initial Results of a Phase II Trial

In-field high-grade glioma (HGG) recurrence is a common challenge with limited treatment options, including re-irradiation (re-RT). Delineating re-RT target volumes is especially challenging in the setting of the VEGF-inhibitor bevacizumab, which can produce an MRI pseudo response. The radiotracer 18F-DOPA crosses the blood brain barrier and demonstrates high uptake in tumor but low uptake in normal tissue. We hypothesized that utilizing 18F-DOPA-PET with MRI for target delineation of recurrent HGG would improve progression free survival at 3 months (PFS3) compared to historical controls treated with systemic therapy only.Adults with recurrent or progressive HGG previously treated with radiation were eligible for this single-arm, phase II prospective trial. A sample size of 20 was calculated to detect a 20% improvement from the historical control PFS3 of 20%, with a power of 85.9% (alpha 0.186). Re-RT dose was 35 Gy in 10 fractions. The target volume was MRI T1 contrast-enhancement defined tumor plus 18F-DOPA-PET defined tumor (tumor/normal ratio > 1.5). Concurrent treatment with bevacizumab was encouraged but not required. Patients were followed at 1 and 3 months (primary endpoint), then every 2 months until 2 years or progression, defined by RANO criteria.Twenty patients completed treatment per protocol. Fifteen (75%) were male. Median age was 53 (range 38-69). Diagnosis was most commonly glioblastoma, IDH-wildtype (60%) or glioblastoma, IDH-mutant (20%). Prior to re-RT, 19 (95%) received previous salvage treatments including surgery (35%) and systemic therapy (90%). Bevacizumab was used prior to, during, and immediately following re-RT in 12 (60%), 14 (70%), and 16 (80%) patients, respectively. Median interval between RT courses was 21.5 months (range 5-167), with an interval > 12 months in 85%. Median MRI-defined, PET-defined, and combined tumor volumes were 17 cc (range 0-198), 14 cc (0.2-209), and 23.2 cc (4-258), respectively. MRI-defined volumes were expanded by a median 43% (0-436%) by utilizing 18F-DOPA-PET. PFS3 was 85% (95% CI: 63.2-95.8%), meeting the primary endpoint of PFS3≥40%. At data lock in January 2021 with 9.7 months median follow-up, 17 (85%) had progressed and 13 (65%) had died. Median OS from re-RT was 8.5 months, with 1- and 2-year OS estimates of 31% and 15%, respectively. Median OS from initial diagnosis was 3.7 years. Failure following re-RT was within both the MRI and PET tumor volumes in 75%, MRI only in 13%, PET only in 0%, and neither in 13%. Four (20%) patients experienced grade 3 toxicity, including CNS necrosis (n = 2, both asymptomatic with bevacizumab initiation for radiographic findings), seizures (n = 1), fatigue (n = 1), and nausea (n = 1). No grade 4-5 toxicities were observed.The 18F-DOPA-PET guided re-irradiation for progressive high-grade glioma appears safe and promising for further investigation.

Phase 2 Study of Pomalidomide (CC-4047) Monotherapy for Children and Young Adults With Recurrent or Progressive Primary Brain Tumors.

IntroductionTreatment of recurrent primary pediatric brain tumors remains a major challenge, with most children succumbing to their disease. We conducted a prospective phase 2 study investigating the safety and efficacy of pomalidomide (POM) in children and young adults with recurrent and progressive primary brain tumors.MethodsPatients with recurrent and progressive high-grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), ependymoma, or medulloblastoma received POM 2.6 mg/m2/day (the recommended phase 2 dose [RP2D]) on days 1-21 of a 28-day cycle. A Simon’s Optimal 2-stage design was used to determine efficacy. Primary endpoints included objective response (OR) and long-term stable disease (LTSD) rates. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety.Results46 patients were evaluable for response (HGG, n = 19; DIPG, ependymoma, and medulloblastoma, n = 9 each). Two patients with HGG achieved OR or LTSD (10.5% [95% CI, 1.3%-33.1%]; 1 partial response and 1 LTSD) and 1 patient with ependymoma had LTSD (11.1% [95% CI, 0.3%-48.2%]). There were no ORs or LTSD in the DIPG or medulloblastoma cohorts. The median PFS for patients with HGG, DIPG, ependymoma, and medulloblastoma was 7.86, 11.29, 8.43, and 8.43 weeks, respectively. Median OS was 5.06, 3.78, 12.02, and 11.60 months, respectively. Neutropenia was the most common grade 3/4 adverse event.ConclusionsTreatment with POM monotherapy did not meet the primary measure of success in any cohort. Future studies are needed to evaluate if POM would show efficacy in tumors with specific molecular signatures or in combination with other anticancer agents.Clinical Trial Registration ClinicalTrials.gov, identifier NCT03257631; EudraCT, identifier 2016-002903-25.

Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas

BackgroundOutcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical median overall survival of 5.6 months. Pediatric high-grade gliomas are largely immunologically silent or “cold,” with few tumor-infiltrating lymphocytes. Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue.MethodsWe conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 (107 or 108 plaque-forming units) by controlled-rate infusion over a period of 6 hours. Cohorts 3 and 4 received radiation (5 Gy) to the gross tumor volume within 24 hours after G207 administration. Viral shedding from saliva, conjunctiva, and blood was assessed by culture and polymerase-chain-reaction assay. Matched pre- and post-treatment tissue samples were examined for tumor-infiltrating lymphocytes by immunohistologic analysis.ResultsTwelve patients 7 to 18 years of age with high-grade glioma received G207. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators. Twenty grade 1 adverse events were possibly related to G207. No virus shedding was detected. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); as of June 5, 2020, a total of 4 of 11 patients were still alive 18 months after G207 treatment. G207 markedly increased the number of tumor-infiltrating lymphocytes.ConclusionsIntratumoral G207 alone and with radiation had an acceptable adverse-event profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunologically “cold” tumors to “hot.” (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.)

Oncolytic Herpes Virus Shrinks Pediatric Gliomas.

In a small trial involving children with progressive high-grade gliomas, direct infusions of a genetically engineered strain of herpes simplex virus elicited responses in 11 of 12 recipients. The therapy also led to more than a doubling in average patient survival compared with historical expectations.

QOLP-23. PHASE II RANDOMISED PLACEBO-CONTROLLED DOUBLE-BLIND STUDY OF ACETAZOLAMIDE VERSUS PLACEBO FOR CEREBRAL OEDEMA IN RECURRENT AND/OR PROGRESSIVE HIGH-GRADE GLIOMA REQUIRING TREATMENT WITH DEXAMETHASONE

Abstract INTRODUCTION Symptoms of raised intracranial pressure (ICP) in recurrent or progressive high-grade glioma (HGG) generally require corticosteroid treatment, often causing toxicity with variable effects on reversing ICP symptoms. Acetazolamide reduces ICP in other clinical settings including case series in glioma. AIM To explore whether addition of oral acetazolamide enables safe dexamethasone dose reduction in management of raised ICP in recurrent and/or progressive HGG. METHODS Participants had recurrent, progressive and/or persistent residual HGG requiring recommencement of dexamethasone, dose increase or dexamethasone dependency; prior/current bevacizumab was an exclusion. Eligible participants were randomised 1:1 to acetazolamide 250mg twice daily or placebo for 8 weeks. Standardised protocols were used for dexamethasone dose changes in both arms, with planned dose decrease from day 5 once ICP symptoms were stable. The primary endpoint was a composite of dexamethasone dose reduction and stability of performance status. Secondary endpoints included toxicity and feasibility (accrual and compliance). RESULTS Thirty participants of a planned sample of 84 were enrolled (mean age 58 y (32-89)) from 7 Australian sites. The mean baseline dexamethasone dose was 6.2mg (4-16mg). Mean duration on treatment was 38 days (4-57) in placebo group and 31 days (3-60) in acetazolamide group, with 9 participants (30%) completing all study treatment (6 placebo, 3 acetazolamide). Study withdrawal was due to adverse events (n=6 (1 placebo, 5 acetazolamide)) and disease progression (n=6 (3 per arm)). Four participants (13%) (2 per arm) were stable responders meeting the primary endpoint criteria (≥50% corticosteroid dose reduction from baseline by 28 days maintained for 7 days, and no deterioration in performance status). Ten participants experienced a total of 13 serious adverse events (acetazolamide arm: 5 participants (33%), 6 events, 2 related). DISCUSSION The addition of acetazolamide did not facilitate dexamethasone reduction. The study closed early due to poor accrual and increasing availability of bevacizumab.

NCMP-09. POSTMORTEM STUDY OF ORGAN SPECIFIC TOXICITY IN GLIOBLASTOMA PATIENTS TREATED WITH A COMBINATION OF TEMOZOLOMIDE, BEVACIZUMAB AND IRINOTECAN

Abstract Combined chemotherapy with temozolomide (TMZ), bevacizumab (BEV) and irinotecan (IRI) [TBI] has been used in patients with recurrent or progressive high-grade gliomas. Patients tolerated the regimen well with increased frequency of reversible clinical myelosuppression (CM), hypertension and proteinuria. However, organ-specific toxicities have never been evaluated by post-mortem examination. From 2009 to 2019, post-mortem examinations were performed in seventy-six decedents, including gliomas (N=68, 44/M and 24/F, median age: 59, ranging 23–80 years old) and brain metastases (N=8, 5/M and 3/F, ranging 39–75 years old). Twenty-four glioma subjects were treated with 1–25 cycles TBI (median 5.5) at glioma recurrence. All subjects’ clinical information, treatment histories and adverse events were collected. Five (7.7%, 5/65) glioma decedents (excluding three glioma patients who never received TMZ) permanently discontinued TMZ due to severe CM during concurrent chemoradiation therapy. There is no significantly elevated severity of CM from TBI when compared to standard of care therapies, nor when comparing extended TMZ treatment to the standard 12 cycles of TMZ. However, exposure to IRI significantly increased the CM occurrence (p&amp;lt; 0.05). Among glioma decedents, the most common cause of death was tumor progression (63.2 %, N=43), followed by aspiration pneumonia (48.5%, N=33). No deaths were attributed to acute toxicity from TBI. An electromicroscopic (EM) examination was performed in addition to routine autopsy procedures to investigate the cause of hypertension and proteinuria frequently developing in patients received BEV therapy. Ultrastructural evidence of thrombotic microangiopathy was observed in the kidneys among BEV users; however, it is difficult to conclude such changes were related to BEV due to rapid autolytic changes and artifacts. CONCLUSION: IRI, not the extended use of TMZ, significantly increased the frequency of reversible CM in recurrent glioma patients. There are no unexpected adverse events or organ-specific toxicities detected among glioma decedents who received the TBI regimen.

Permanent iodine-125 brachytherapy for patients with progressive or recurrent high-grade gliomas

BackgroundThe prognosis of patients with progressive or recurrent high-grade gliomas (HGGs) after surgery remains poor. Iodine-125 brachytherapy is emerging as a salvage method for the treatment of gliomas. This study aimed to investigate whether permanent iodine-125 brachytherapy could be used as an effective therapeutic method even without radiotherapy and/or chemotherapy for progressive or recurrent HGG after gross total resection.MethodsBetween March 2004 and August 2016, 58 patients with progressive or recurrent HGG after gross total resection were included in this study. Twenty-nine patients underwent radiotherapy and/or chemotherapy and then permanent iodine-125 brachytherapy (SRCI group). Twenty-nine patients underwent permanent iodine-125 brachytherapy alone (SI group). Follow-up was carried out at 1, 3, and 6 months and then at 1, 2, 3, and 5 years after iodine-125 implantation. The median overall survival (OS) and progression-free survival (PFS), procedure-related complications and clinical outcomes were evaluated.ResultsNo procedure-related fatal events happened. The temporary morbidity rate was 11.9%. The median OS and PFS for patients in the SI group were 22 and 8 months compared with 21 and 7 months in the SRCI group. No significant differences were found. Age and Karnofsky Performance Status (KPS) were independent prognostic factors for OS. Age, KPS and histology were independent prognostic factors for PFS.ConclusionsPermanent iodine-125 brachytherapy could be used as an effective therapeutic method even without radiotherapy and/or chemotherapy for progressive or recurrent HGG after gross total resection.

Cancer Stem Cell Chemotherapeutics Assay for Prospective Treatment of Recurrent Glioblastoma and Progressive Anaplastic Glioma: A Single-Institution Case Series

BACKGROUND: Chemotherapy-resistant cancer stem cells (CSC) may lead to tumor recurrence in glioblastoma (GBM). The poor prognosis of this disease emphasizes the critical need for developing a treatment stratification system to improve outcomes through personalized medicine. METHODS: We present a case series of 12 GBM and 2 progressive anaplastic glioma cases from a single Institution prospectively treated utilizing a CSC chemotherapeutics assay (ChemoID) guided report. All patients were eligible to receive a stereotactic biopsy and thus undergo ChemoID testing. We selected one of the most effective treatments based on the ChemoID assay report from a panel of FDA approved chemotherapy as monotherapy or their combinations for our patients. Patients were evaluated by MRI scans and response was assessed according to RANO 1.1 criteria. RESULTS: Of the 14 cases reviewed, the median age of our patient cohort was 49 years (21–63). We observed 6 complete responses (CR) 43%, 6 partial responses (PR) 43%, and 2 progressive diseases (PD) 14%. Patients treated with ChemoID assay-directed therapy, in combination with other modality of treatment (RT, LITT), had a longer median overall survival (OS) of 13.3 months (5.4-NA), compared to the historical median OS of 9.0 months (8.0–10.8 months) previously reported. Notably, patients with recurrent GBM or progressive high-grade glioma treated with assay-guided therapy had a 57% probability to survive at 12 months, compared to the 27% historical probability of survival observed in previous studies. CONCLUSIONS: The results presented here suggest that the ChemoID Assay has the potential to stratify individualized chemotherapy choices to improve recurrent and progressive high-grade glioma patient survival. Importance of the StudyGlioblastoma (GBM) and progressive anaplastic glioma are the most aggressive brain tumor in adults and their prognosis is very poor even if treated with the standard of care chemoradiation Stupp's protocol. Recent knowledge pointed out that current treatments often fail to successfully target cancer stem cells (CSCs) that are responsible for therapy resistance and recurrence of these malignant tumors. ChemoID is the first and only CLIA (clinical laboratory improvements amendment) -certified and CAP (College of American Pathologists) -accredited chemotherapeutic assay currently available in oncology clinics that examines patient's derived CSCs susceptibility to conventional FDA (Food and Drugs Administration) -approved drugs. In this study we observed that although the majority of our patients (71.5%) presented with unfavorable prognostic predictors (wild type IDH-1/2 and unmethylated MGMT promoter), patients treated with ChemoID assay-directed therapy had an overall response rate of 86% and increased median OS of 13.3 months compared to the historical median OS of 9.1 months (8.1–10.1 months) previously reported [1] suggesting that the ChemoID assay may be beneficial in personalizing treatment strategies.

Lysosomal acid lipase deficiency across ages: Unraveling the clinical spectrum of an under-recognized genetic disorder

Based on the effective radiological responses, bevacizumab (BEV) has been widely used in the treatment of recurrent high-grade glioma. Although the current standard dose is 5 mg/kg/week, the optimal dosage of BEV is controversial, as few dose-response studies have been performed in recent years. Therefore, we conducted a meta-analysis to explore the value of reduced-dose bevacizumab versus standard-dose bevacizumab in recurrent high-grade glioma treatment.Three major electronic databases (PubMed, EMBASE and the Cochrane Library) were searched for eligible documents published before February 2020. Literature on low-dose bevacizumab versus conventional dose in progressive high-grade glioma was included, and the endpoints of eligible researches should be progression-free survival (PFS) and overall survival (OS). All available data were collected and then analyzed with Stata software.Four cohort studies were evaluated, including 552 patients (reduced-dose BEV group: 257, standard-dose BEV group: 295). Low dose BEV seems to slightly improve survival compared to conventional dose as HR < 1 indicates a protective effect, but no significant differences in OS (HR 0.77; 95 % CI 0.53–1.10; P = 0.151) and PFS (HR 0.66; 95 % CI 0.37–1.20; P = 0.175) were found between the two groups in this study.Reduced-dose bevacizumab schedule resulted in similar OS and PFS to standard-dose bevacizumab in recurrent high-grade glioma, with less side effects and less cost of treatment. Therefore, low-dose bevacizumab represents a promising therapeutic option for recurrent high-grade glioma patients. Further prospective randomized trials are needed to confirm our results.

QOLP-05. PREDICTING SURVIVAL WITH THE HEIDELBERG PROGNOSTIC MODEL AFTER SALVAGE STEREOTACTIC RADIOSURGERY OF PREVIOUSLY IRRADIATED PROGRESSIVE HIGH-GRADE GLIOMAS

Abstract BACKGROUND The concept of repeat radiotherapy for previously irradiated, progressive high-grade gliomas (PHGG) is intuitively rational for a disease that has the potential to be a life-threatening illness and seriously affect the quality of remaining life. Recently, a simplified method of prognosis prediction (the Heidelberg prognostic model/HPM) was developed to evaluate survival after re-irradiation of PHGGs. OBJECTIVE This retrospective study aimed to assess whether salvage stereotactic radiosurgery (SSRS) is worthwhile in patients with PHGGs, and to determine which individuals are likely to benefit from retreatment using the HPM. METHODS Three hundred eighty-three people were diagnosed with intracranial glioma between 2000 and 2010 at our institution. From this population, 25 patients (7%) who had a history of prior irradiation and underwent SSRS for PHGGs formed the subjects of this clinical audit. In the HPM system, scores were assigned for clinicopathological features such as age, histology and interval duration between treatments. There were five and 20 patients with HPM determined low and high prognostic scores, respectively. The mean follow-up period was 9.9 months. RESULTS Overall median survival (MS) was 7 months, and the 6, 12- and 24-months crude survival rates (CSR) were 60%, 28% and 16%, respectively. The MS and CSRs for the low scoring patients were 20 months, 100%, 100% and 20%, respectively; for the 20 high-scoring individuals, the corresponding findings were 8 months, 75%, 35% and 10%, respectively. Among the evaluable 11 people, the quality of life was acceptable in approximately half of the cases. Local recurrence rate after SSRS was 12%. Adverse-related events were not observed. CONCLUSION A trend towards improved survival was observed in the HPM low-scoring patients. More documentation of favorable effects is required to support the useful role of SSRS as second line treatment of PHGGs.

STEM-13. CANCER STEM CELL CYTOTOXICITY ASSAY-GUIDED TREATMENT IN RECURRENT GLIOBLASTOMA AND PROGRESSIVE ANAPLASTIC GLIOMA

Abstract BACKGROUND The presence of chemotherapy-resistant cancer stem cells (CSC) leading to tumor recurrence is postulated to be one of the major factors in the poor response to the current standard of care treatments in progressive high-grade gliomas. Unfortunately, in spite of several new drug discoveries for other tumor types, not many advances have been reported for this disease and therefore recurrent and progressive high-grade glioma survival remains dismal. METHODS We have used a CLIA and CAP accredited Cancer Stem Cell Cytotoxicity Assay(ChemoID) to guide most effective chemotherapy treatments from a panel of FDA approved drugs or their combinations for 12 recurrent glioblastoma (GBM) patients and 2 progressive anaplastic gliomas, all eligible to receive a stereotactic biopsy. Patients were evaluated by MRI scans and response was assessed according to RANO criteria. RESULTS The median age of our patient cohort was 49 years (21–63), with 11 males (79%) and 3 females (21%). We observed 6 complete responses (CR) 43%, 6 partial responses (PR) 43%, and 2 progressive diseases (PD) 14%. Of note, the two PD were observed in patients that could not be treated with assay recommended therapy due to their health status. Patients treated with ChemoID assay-directed therapy had a longer median overall survival (OS) of 13.3 months (5.4-NA) compared to the historical median OS of 9.0 months (8.0–10.8 months) previously reported (1). Notably, our recurrent and progressive high-grade glioma patient cohort treated with assay-guided therapy had a 57% probability to survive at 12 months, compared to the 27% historical probability of survival at 12 months observed in previous studies (1). CONCLUSIONS The data suggests that the ChemoID Cancer Stem Cell Cytotoxicity Assay has the potential to help guide individualized chemotherapy choices to improve recurrent and progressive high-grade glioma patient outcome. 1) Friedman, H.S. et. al. JCO2009 27:28, 4733–4740.

P14.60 FET PET response upon radiochemotherapy followed by Tumor Treating Fields (TTFields) in a patient with progressive high-grade glioma

Abstract BACKGROUND The addition of Tumor Treating Fields (TTFields) to the first-line therapy in glioblastoma (GBM) demonstrated significantly improved progression free survival, overall survival and longterm survival rates in the EF-14 phase 3 trial. However, responder analysis of patients with recurrent GBM (rGBM) treated with TTFields monotherapy (in the EF-11 trial) revealed delayed response monitored by MRI analysis. More recent data suggests that O-(2-18F-fluoroethyl)-L-tyrosine (FET) PET may add valuable information for monitoring therapy response of glioblastoma patients treated with TTFields. Here, we report on FET PET response in a patient with progressive anaplastic astrocytoma WHO grade III (AA) treated with TTFields in combination with temozolomide (TMZ) chemotherapy. METHODS We present a 38-year old patient with an initial diagnosis of a diffuse astrocytoma WHO grade II in 2011, and malignisation to an AA on progression. The treatment regimen included initially radio-chemotherapy (RCT) with TMZ. On further progression of the AA in 2017, TTFields were added to another 6 cycles of TMZ. Several FET PET scans for differentiation of tumor progression from treatment-related changes were performed over time. The definitive diagnosis (tumor progression and grading) was confirmed by histopathology after stereotactic biopsy (SB). RESULTS In 2012, the patient was first diagnosed with a low grade astrocytoma WHO grade II of the right frontal, temporal and parietal lobe including infiltration of thalamus and corpus was confirmed by SB, followed by irradiation. On progression in 2015, a FET PET Scan showed FET avidity in all tumor affected regions of the brain. SB confirmed an AA, while FET PET scans showed only a mild response in the temporoparietal region after 6 cycles of TMZ. In 2017, the next progression without further malignisation was confirmed by SB and treated RCT with 41.4 Gy and TMZ chemotherapy, followed by application of TTFields with an average usage rate of 85.7 % over 6 months. Thus, the TTFields adherence was well above the independent prognostic threshold of 75 %. No additional adverse events due to the combined therapy of TTFields and TMZ were observed. Due to a new contrast enhancing lesion in the right frontal lobe (10x7mm), another FET PET scan was performed 1.5 years later. In this scan, obtained after combined TTFields and RCT therapy a strong response regarding FET avidity was observed. CONCLUSION In summary, FET PET is able to add important additional information for evaluation of treatment response in high grade glioma patients, in particular for TTFields treated patients, while adding TTFields to radiochemotherapy might even enhance treatment response of high grade glioma. Further studies might elucidate the role of FET PET imaging for therapy monitoring in high grade glioma patients treated with TTFields.

Phase 1/2a study of once daily oral BAL101553, a novel tumor checkpoint controller (TCC), in adult patients with progressive or recurrent glioblastoma (GBM) or high-grade glioma.

2025 Background: BAL101553 (prodrug of BAL27862) is a novel TCC that promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 is a lipophilic, small molecule shown in rodents to penetrate the brain (brain/plasma ratio around unity), with promising antitumor activity in orthotopic preclinical GBM models as monotherapy or in combination with radiotherapy (RT) with or without temozolomide. In this ongoing study (NCT02490800, CDI-CS-002), daily oral BAL101553 was initially examined in solid-tumor patients, with an MTD of 16 mg/d and DLTs of G4 hyponatremia and G2 hallucinations (Lopez 2018, JCO 36, 2018, suppl. A2530). Subsequently the study was expanded by including a separate cohort of patients with progressive or recurrent GBM or high-grade glioma (Ingles Garces 2017, JCO 35, 2018, suppl. TPS2601). Methods: Patients with histologically-confirmed GBM or high-grade glioma, with progressive or recurrent disease after prior RT with/without chemotherapy, received once-daily oral BAL101553 (28-day cycles) in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD). Adverse events were assessed by CTCAE v4.03 grade (G), and tumor response by RANO every two cycles. Pharmacokinetics (PK) were evaluated on Day 1 of Cycles 1 and 2. Results: In the ongoing study, 23 pts (13M/10F; median age 50 y), median (min–max) number of prior regimens = 2 (1–5), received doses of 8, 15, 20, 25 or 30 mg oral BAL101553 once daily. One DLT of reversible G2 depression and fatigue occurred at 20 mg. Both mean Cmax and AUC increased with dose between 8 and 30 mg. The PK exposure in GBM patients was lower than for solid tumor patients, in particular at 20 and 25 mg. At 25 mg/d (n = 3), one patient with IDH-mutated GBM had a partial response (63% area reduction per RANO) and continues on study &gt; 8 months, and another patient had stable disease for 5 months. At 15–20 mg/d, stable disease was observed in 3/10 patients. Conclusions: The current data in patients with GBM or high-grade glioma suggest that BAL101553 is well tolerated at dose levels above the MTD established in patients with advanced solid tumors, and shows indications of clinical activity. Clinical trial information: 02490800.