Concomitant Temozolomide Research Articles

Phase I/II study testing the combination of AGuIX nanoparticles with radiochemotherapy and concomitant temozolomide in patients with newly diagnosed glioblastoma (NANO-GBM trial protocol)

BackgroundDespite standard treatments including chemoradiotherapy with temozolomide (TMZ) (STUPP protocol), the prognosis of glioblastoma patients remains poor. AGuIX nanoparticles have a high radiosensitizing potential, a selective and long-lasting accumulation in tumors and a rapid renal elimination. Their therapeutic effect has been proven in vivo on several tumor models, including glioblastoma with a potential synergetic effect when combined with TMZ based chemoradiotherapy, and they are currently evaluated in 4 ongoing Phase Ib and II clinical trials in 4 indications (brain metastases, lung, pancreatic and cervix cancers) (> 100 patients received AGuIX). Thus, they could offer new perspectives for patients with newly diagnosed glioblastoma. The aim of this study is to determine the recommended dose of AGuIX as a radiosensitizer in combination with radiotherapy and TMZ during the concurrent radio-chemotherapy period for phase II (RP2D) and to estimate the efficacy of the combination.MethodsNANO-GBM is a multicenter, phase I/II, randomized, open-label, non-comparative, therapeutic trial. According to a dose escalation scheme driven by a TITE-CRM design, 3 dose levels of AGuIX (50, 75 and 100 mg/kg) will be tested in phase I added to standard concomitant radio-chemotherapy. Patients with grade IV glioblastoma, not operated or partially operated, with a KPS ≥ 70% will be eligible for the study. The primary endpoints are i) for phase I, the RP2D of AGuIX, with DLT defined as any grade 3–4 NCI-CTCAE toxicity and ii) for phase II, the 6-month progression-free survival rate. The pharmacokinetics, distribution of nanoparticles, tolerance of the combination, neurological status, overall survival (median, 6-month and 12-month rates), response to treatment, and progression-free survival (median and 12-month rates) will be assessed as secondary objectives. Maximum sixty-six patients are expected to be recruited in the study from 6 sites.DiscussionThe use of AGuIX nanoparticles could allow to overpass the radioresistance to the reference treatment of newly diagnosed glioblastomas that have the poorest prognosis (incomplete resection or biopsy only).Trial registrationClinicaltrials.gov: NCT04881032, registered on April 30, 2021. Identifier with the French National Agency for the Safety of Medicines and Health Products (ANSM): N°Eudra CT 2020-004552-15. Protocol: version 3, 23 May 2022.

872 Disruption of KIF3a Increases Sensitivity of Primary Glioblastoma Cells to Temozolomide and Radiotherapy

INTRODUCTION: Glioblastoma (GBM) is the most common primary malignant brain tumor, comprising 14.3% of all intracranial neoplasms and 49.1% of all malignant brain tumors. The current standard of care for newly diagnosed glioblastoma is maximal safe resection, 60 Gy of radiotherapy over a 6-week period, plus concomitant daily temozolomide, followed by adjuvant temozolomide over 6 months. Nonetheless, median overall and 5-year survival are only 15 months and 5%, respectively. Primary cilia are microtubule-based organelles that protrude from the apical surface of nearly all mammalian cells. They are critical to many canonical signaling pathways and are closely related to the cell cycle. They have been implicated in the formation and progression of many malignancies and are associated with resistance to chemoradiotherapy. METHODS: Patient-derived GBM cell lines were transduced with lentiviral particles to produce stable cell lines deficient in proteins essential for primary cilia regulation. Cell proliferation assays were used to assess sensitivity of each knockdown to temozolomide and radiotherapy. RESULTS: Proliferation of KIF3A knockdown cells was significantly decreased compared to control lines after radiotherapy (P = 0.009). GBM cells with disrupted primary cilia were more frequently found in the G2/M phase potentially explaining the increase in sensitivity. KIF3A depleted cells also displayed improved response to temozolomide. MGMT protein expression was decreased in these cells, providing a potential mechanism for the decrease in proliferation. This finding reveals a new relationship between primary cilia and MGMT, an extremely important biomarker that is commonly used to predict the efficacy of alkylating chemotherapy. CONCLUSIONS: Collectively, our findings provide strong evidence that primary cilia play an important role in resistance to the current standard treatment of GBM and identify KIF3A as a potential sensitizer to chemoradiation in GBM.

Highlighted Advances in Therapies for Difficult-To-Treat Brain Tumours Such as Glioblastoma.

Glioblastoma multiforme (GBM) remains a challenging disease, as it is the most common and deadly brain tumour in adults and has no curative solution and an overall short survival time. This incurability and short survival time means that, despite its rarity (average incidence of 3.2 per 100,000 persons), there has been an increased effort to try to treat this disease. Standard of care in newly diagnosed glioblastoma is maximal tumour resection followed by initial concomitant radiotherapy and temozolomide (TMZ) and then further chemotherapy with TMZ. Imaging techniques are key not only to diagnose the extent of the affected tissue but also for surgery planning and even for intraoperative use. Eligible patients may combine TMZ with tumour treating fields (TTF) therapy, which delivers low-intensity and intermediate-frequency electric fields to arrest tumour growth. Nonetheless, the blood-brain barrier (BBB) and systemic side effects are obstacles to successful chemotherapy in GBM; thus, more targeted, custom therapies such as immunotherapy and nanotechnological drug delivery systems have been undergoing research with varying degrees of success. This review proposes an overview of the pathophysiology, possible treatments, and the most (not all) representative examples of the latest advancements.

Early Gamma Knife Therapy (Without EBRT) in Operated Patients of Glioblastoma Multiforme.

The standard therapy for glioblastoma (GBM) has been external beam radiotherapy (EBRT) with concomitant temozolomide (TMZ) given for six cycles, after maximum possible surgical resection although recurrences after chemoradiation are mostly in-field. To compare the effects of early GKT (without EBRT) along with TMZ to those receiving standard chemoradiotherapy (EBRT + TMZ) after surgery. This was a retro-prospective study on histologically proven GBMs operated at our center between January 2016 and November 2018. The EBRT group consisted of 24 patients who received EBRT + TMZ for six cycles. The GKT arm consisted of 13 consecutive patients who received Gamma Knife within 4 weeks of surgery along with lifelong temozolomide. Patients were followed up every 3 months with CEMRI brain and PET-CT. The primary endpoint was overall survival (OS) with progression-free survival (PFS) being the secondary endpoint. At a mean follow-up of 13.7 months, the median overall survivals in GKT and EBRT groups were 11.07 and 13.03 months, respectively (HR = 0.59; P value = 0.19; 95% CI: 0.27-1.29). The median PFS for GKT group was 7.03 months (95% CI: 4.17-17.3) as compared to 11.07 months (95% CI: 5.33-14.03) for the EBRT group. There was no statistical difference in the PFS or OS between the GKT and EBRT groups. Our study shows that Gamma Knife therapy (without EBRT) to residual tumor/tumor bed after primary surgery with concurrent temozolomide has similar progression-free (PFS) and overall survival (OS) rates when compared to conventional treatment (EBRT).

Impact of Extended Adjuvant Temozolamide Beyond 6 Months in the Management of Glioblastoma Patients.

Our study aimed to assess the benefit of prolonging adjuvant temozolomide (TMZ) therapy beyond 6 cycles in glioblastoma multiform patients. The medical records of 329 patients in 2 cancer centers in Egypt were reviewed from January 2008 to December 2018 who were diagnosed with diffuse gliomas. Data were collected on patient demographics, presenting complaints, tumor size, treatment modalities (extent of surgery, radiotherapy dose and technique, concomitant TMZ, and the number of adjuvant TMZ cycles), and reported adverse events. In the studied cohort, 105 patients were treated with adjuvant TMZ, 33 patients received <6 cycles (TMZL), 41 patients received the standard 6 cycles (TMZS), and 31 patients received >6 cycles (TMZE). Our results showed the median overall survival in the TMZL arm was 8.47 months compared with 15.83 months in the TMZS arm and 27.33 months in the TMZE arm ( P < 0.001). Furthermore, a median progression-free survival of 6.35 months was reported in the TMZL group versus, 12.7 and 22.90 months in (TMZS) and (TMZE) groups, respectively( P < 0.001). In the multivariate analysis, the extended adjuvant TMZ with a hazard ratio of 3.106 (95% CI: 2.43-14.46; P < 0.001) was statistically significantly associated with a better outcome. Extended adjuvant TMZ therapy beyond 6 cycles may significantly improve the progression-free survival and overall survival in patients with glioblastoma multiform.

Survival in a consecutive series of 467 glioblastoma patients: Association with prognostic factors and treatment at recurrence at two independent institutions.

Therapy of recurrent glioblastoma (GBM) is challenging due to lack of standard treatment. We investigated physicians' treatment choice at recurrence and prognostic and predictive factors for survival in GBM patients from Norway's two largest regional hospitals. Clinicopathological data from n = 467 patients treated at Haukeland and Oslo university hospitals from January 2015 to December 2017 was collected. Data included tumour location, promoter methylation of O6 methylguanine-DNA methyltransferase (MGMT) and mutation of isocitrate dehydrogenase (IDH), patient age, sex, extent of resection at primary diagnosis and treatment at successive tumour recurrences. Cox-proportional hazards regression adjusting for multiple risk factors was used. Median overall survival (OS) was 12.1 months and 21.4% and 6.8% of patients were alive at 2 and 5 years, respectively. Median progression-free survival was 8.1 months. Treatment at recurrence varied but was not associated with difference in overall survival (OS) (p = 0.201). Age, MGMT hypermethylation, tumour location and extent of resection were independent prognostic factors. Patients who received 60 Gray radiotherapy with concomitant and adjuvant temozolomide at primary diagnosis had 16.1 months median OS and 9.3% were alive at 5 years. Patients eligible for gamma knife/stereotactic radiosurgery alone or combined with chemotherapy at first recurrence had superior survival compared to chemotherapy alone (p<0.001). At second recurrence, combination chemotherapy with or without bevacizumab were both superior to no treatment. Treatment at recurrence differed between the institutions but there was no difference in median OS, indicating that it is the disease biology that dictates patient outcome.

Gene enrichment analysis and protein–protein interaction network topology delineates S-Phase kinase-associated protein 1 and catenin beta-1 as potential signature genes linked to glioblastoma prognosis

Background: Glioblastoma (GBM) is the most malignant and accounts for 60% of brain tumors in adults. Current therapy for GBM involves surgical removal of the tumor followed by radiotherapy with concomitant adjuvant therapy temozolomide. Despite improvements in therapy, patient survival remains low. The exact etiology of a brain tumor is uncertain, and numerous unknown genes are involved in the progression of GBM. The aim of the present study was to evaluate various genes involved in GBM through bioinformatic approach. Methods: In the present study, gene expression profile of GSE68424 was retrieved from the GEO database to explore the genes in GBM. Results: Analysis of expression profile data revealed that 33 genes were upregulated and 1189 genes were downregulated based on the log2 fold change cut-off criteria. The genes S-Phase kinase-associated protein 1 (SKP1) and Catenin beta-1 (CTNNB1) have been linked to GBM prognosis. Conclusion: SKP1 and CTNNB1 were identified as a candidate gene for GBM study as a result of these findings. Catenin beta-1 was the protein with the highest closeness centrality value and is the key component of canonical Wnt signaling downstream pathway. More study is needed to establish the molecular function of SKP1 and CTNNB1 in GBM development, as well as the biomarker's specificity and sensitivity.

Impact of EGFRA289T/V mutation on relapse pattern in glioblastoma

Molecular factors influence relapse patterns in glioblastoma. The hotspot mutation located at position 289 of the extracellular domain of the epidermal growth factor receptor (EGFRA289mut) is associated with a more infiltrative phenotype. The primary objective of this study was to explore the impact of the EGFRA289 mutation on the pattern of relapse after chemoradiotherapy-based treatment of patients suffering from newly diagnosed glioblastoma. An ancillary study from a prospective cohort of patients suffering from glioblastoma was conducted. All patients received radiotherapy and concomitant temozolomide. The population was divided into two groups according to EGFRA289 status (mutated versus wild-type). The primary endpoint was the overlap score (varying from 0 to 1) between the initial irradiated tumor volume (Vinit) and the relapse volume (Vr). Secondary endpoints explored the impact of EGFRA289mut on survival. One hundred twenty-eight patients were included and analyzed: 11% had EGFRA289mut glioblastoma (n= 14/128). EGFRA289mut glioblastomas had a relapse pattern that was more marginal than EGFRA289wt glioblastomas: a median overlap score Vinit/Vr of 0.96 was observed in the EGFRA289mut group versus 1 in the EGFRA289wt group (P= 0.05). Half of the population with EGFRA289mut tumor (n= 7/14) had a marginal relapse (i.e. overlap scoreVr/Vinit ≤ 0.95) compared to 23.7% (n= 27/114) in the EGFRA289wt group, P= 0.035. EGFRA289mut did not influence survival. We highlighted a link between the EGFRA289 mutation and the relapse pattern in glioblastoma. The independent role of EGFRA289mut and its clinical implication should now be explored in further studies.

Standard deviations of MR signal intensities show a consistent trend during imaging follow-ups for glioblastoma patients when corrected for non-biological heterogeneity due to hardware and software variation

IntroductionGlioblastoma multiforme (GBM) has a poor prognosis in spite of advanced MRI guided treatments today. Routine MRI using conventional T1 or advanced permeability based MRI of GBM often does not adequately represent changing tumor phases or overall survival. In this work, region of interest (ROI) based tissue MR standard deviation (SD) is demonstrated as an important MRI variable that could be a potential biomarker of GBM heterogeneity and radioresistance. Materials and methodsMRI characterization is often qualitative and lacks reproducibility. Using standardized MRI phantoms we have normalized retrospective records of 12 radioresistant GBM patients that underwent radiation therapy (RT) with concomitant and adjuvant temozolomide (TMZ) chemotherapy followed by serial MR imaging with gadolinium contrast. Results and discussionWe have identified key variables like hardware, software and protocol variation and have standardized those using test phantoms at five MR systems. We suggest GBM growth during the treatment period can be linked to normalized MRI signal and its fluctuations from session to session and from magnet to magnet by using an ROI derived standard deviation that corresponds to heterogeneity of the tumor MRI signal and changes in magnetic susceptibility. The time period observed in our patient group for peak standard deviations is approximately halfway through the tumor course and may correspond to a growth of more aggressive MES subtype of cells. To model the GBM heterogeneity we performed in vitro T1 weighted inversion recovery MRI experiments at 3 T for porous media of silicate particles in 1% aq solution of Gadavist and linked SD with particle size and local gadolinium volume within porous media. Such in vitro models mimic the increased SD in radioresistant GBM and as a novel contribution suggest that finer texture with high surface area might arise approximately halfway through the overall survival duration in GBM. ConclusionStandard deviation as a measure of magnetic susceptibility may be collectively linked to the changes in texture, cell fractions (biological) and trapped contrast media (vascular as well as artifactual consequences) and should be evaluated as a potential biomarker of GBM aggressiveness than the overall MRI signal intensity from a GBM.

ACT-8 A RANDOMIZED PHASE III STUDY OF HYPOFRACTIONATED RADIOTHERAPY COMBINED WITH TEMOZOLOMIDE IN ELDERLY PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA: JCOG1910 (AGEDGLIO-PIII)

Abstract Background The current standard treatment for elderly patients with newly diagnosed glioblastoma is surgery followed by short-course radiotherapy (40 Gy in 15 fractions) with temozolomide. Further reduction of fractionation is expected to reduce the burden for elderly patients without decreasing therapeutic efficacy. Methods This multi-institutional randomized phase III trial was commenced to confirm the non-inferiority of radiotherapy comprising 25 Gy in 5 fractions with concomitant and adjuvant temozolomide over 40 Gy in 15 fractions with concomitant and adjuvant temozolomide in terms of overall survival (OS) in elderly patients aged 71 or older with newly diagnosed glioblastoma. The primary endpoint is OS, and the secondary endpoints are progression-free survival, frequency of adverse events, proportion of Karnofsky performance status preservation, and proportion of health-related quality of life preservation. MGMT promoter methylation was included as an adjustment factor, and tumor specimen have been collected soon after the tumor resection and molecular diagnosis has been made centrally before randomization. A total of 270 patients will be accrued from 55 Japanese institutions in 4 years and follow-up will last 2 years. Results More than a half of patients (160 /270 cases) have been recruited between August 2020 and July 2022. Molecular diagnosis was made all but one cases, and diagnosis was made centrally within around 7 days after receiving the tumor specimen. There were one grade 4 severe adverse event and one treatment related death. Discussion Registration has been made smoothly without substantial delay due to central molecular diagnosis. The study has been safely performed for elderly patients. If the primary endpoint is met, hypofractionated radiotherapy comprising 25 Gy in 5 fractions with concomitant and adjuvant temozolomide will be a standard of care for elderly patients with newly diagnosed glioblastoma.

48P Phase II trial on vaccination with autologous dendritic cells loaded with autologous tumour homogenate in resected glioblastoma (COMBI-GVAX): Clinical results of the first step

Glioblastoma (GBM) is a poor prognosis malignant grade IV glioma. After surgical resection, standard therapy consists of concomitant radiotherapy (RT) and temozolomide (TMZ) followed by TMZ alone. Multiple phase I/II trials and at least 3 meta-analysis showed improved survival (OS) and progression free survival (PFS) with dendritic cell (DC) vaccination in high-grade gliomas (HGGs) patients (pts). In those developing antitumor immunity, DC vaccine increases the amount of intratumoral activated cytotoxic T lymphocytes and decreases the number of FoxP3 positive regulatory T cells.

DDDR-17. CHEMOTHERAPEUTIC STRESS INDUCES NONCANONICAL HIF1Α SIGNALING UNDER NORMOXIA IN GLIOBLASTOMA DRIVING THERAPEUTIC RESISTANCE

Abstract Glioblastoma (GBM) is an aggressive brain tumor with no cure. Standard treatment includes adjuvant, concomitant temozolomide (TMZ) and radiation, but most patients do not survive more than 15 months. Tumor adaptations to temozolomide (TMZ) contribute to glioblastoma (GBM) chemoresistance and recurrence, and hypoxia inducible factor subunit alpha (HIF1α) and downstream effectors are implicated in attenuated therapeutic responses. We have previously shown that TMZ-dependent hijacking of HIF1α signaling under normoxia is independent from physiological hypoxia in the tumor core. Our results further showed that TMZ promotes HIF1α accumulation enhancing stem-like characteristics of GBM cells driving therapy-resistant populations involved in recurrence. However, noncanonical HIF1α signaling mechanisms are not well understood preventing the success of HIF1α inhibitors in GBM thus far. Here, we investigate how TMZ induces HIF1α in an oxygen-independent manner by characterizing the HIF1a binding profile post-therapy. We cultured patient-derived xenograft (PDX) models of GBM in vitro and found HIF1α expression and hypoxia response element (HRE) activity peak 96h post-therapy using western blot and luciferase assays. Our lab also performed a whole-genome CRISPR-Cas9 knockout screen in GBM cells over 28 days to determine genetic drivers of GBM aggression. HIF1α was found to be particularly enriched in this screen, further supporting the role of chronic hypoxia signaling for GBM proliferation (p-value &amp;lt; 0.05). We show TMZ therapy prevents proteasome-dependent degradation through reduced binding of PHD2 and VHL allowing nuclear translocation of HIF1a through western blot and immunocytochemistry. Thus, we performed immunoprecipitation of HIF1α 96h post-therapy for proteomic characterization to establish how TMZ uniquely regulates HIF1α stabilization in the absence of oxygen tension, and these results will be presented. We will subsequently characterize the regulatory role of TMZ-dependent post-translational modifications to HIF1α. Elucidating the molecular mechanisms of therapy-mediated HIF1α regulation can produce better therapeutic targets and increase TMZ efficacy.

CTNI-21. TROTABRESIB (CC-90010) IN COMBINATION WITH CONCOMITANT TEMOZOLOMIDE PLUS RADIOTHERAPY AND ADJUVANT TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA: UPDATED RESULTS FROM A PHASE 1B/2 STUDY

Abstract Trotabresib, a novel bromodomain and extraterminal protein inhibitor, has demonstrated antitumor activity and blood–brain barrier penetration in patients with high-grade gliomas, and enhanced the antiproliferative effects of temozolomide in preclinical models. CC-90010-GBM-002 (NCT04324840) is a phase 1b/2 study investigating the addition of trotabresib to standard-of-care (SOC) concomitant temozolomide plus radiotherapy and adjuvant temozolomide, followed by maintenance trotabresib, in patients with newly diagnosed glioblastoma. The design of the dose escalation (part A) has been described previously (Vieito M, et al. SNO 2021. Abstract CTNI-51). Primary objectives of part A were to establish the safety, tolerability, and maximum tolerated dose/recommended phase 2 dose (RP2D) of trotabresib. In part A, addition of trotabresib to SOC was safe and well tolerated in the concomitant (N = 14) and adjuvant (N = 18) cohorts; the most frequent grade 3/4 treatment-related adverse event was thrombocytopenia (7/14 and 9/18 patients, respectively). The RP2D for trotabresib was 30 mg/day 4 days on/24 days off in both settings. At data cutoff (February 20, 2022), median duration of treatment was 34 weeks (concomitant cohort) and 33 weeks (adjuvant cohort); progression-free survival data are not yet mature. Trotabresib plasma pharmacokinetics and pharmacodynamics were consistent with monotherapy. At last follow-up, 6 and 5 patients remained on treatment in the concomitant and adjuvant dose-escalation cohorts, respectively, including 1 patient in cycle 20 with ongoing complete response. The ongoing randomized phase 2 dose expansion (part B; planned N = 162) is comparing concomitant trotabresib at the RP2D + SOC followed by adjuvant trotabresib at the RP2D + SOC, followed by maintenance trotabresib 45 mg/day 4 days on/24 days off, versus SOC alone in patients with newly diagnosed IDH–wild-type glioblastoma. Key objectives are to compare progression-free and overall survival, safety, and tolerability. Longer follow-up from part A and the first disclosure of data from part B will be presented.

DNAR-10. THE EFFICACY OF TEMOZOLOMIDE AND LOMUSTINE IN GLIOBLASTOMA CELL LINES MAY BE ENHANCED BY CONCOMITANT TREATMENT WITH TUMOR TREATING FIELDS (TTFIELDS)

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Temozolomide (TMZ) is part of the standard of care for patients with newly diagnosed GBM (ndGBM). Expression of the enzyme MGMT involved in TMZ-induced DNA damage repair is associated with irresponsiveness of some patients to TMZ. The addition of lomustine (CCNU) to TMZ demonstrated clinical benefit in patients with ndGBM. Tumor Treating Fields (TTFields) are electric fields that display anti-mitotic effects and lower expression levels of proteins from the FA-BRCA DNA repair pathway in cancerous cells. TTFields therapy concomitant with TMZ is approved for the treatment of ndGBM. The aim of the current study was to examine the effect of TTFields in conjunction with TMZ and CCNU in GBM cells. Human GBM cell lines with different MGMT expression levels (U-87 MG, LN229, U118, and LN18) were treated with TTFields (0.83 V/cm RMS, 200 kHz) concomitant with TMZ and/or CCNU. Cell counts, colony formation, and apoptosis were used to measure effectiveness. The effect of TTFields with concomitant TMZ was additive in all cell lines, regardless of MGMT expression levels. TTFields in conjunction with CCNU displayed an additive effect in cell lines with high MGMT expression, and tendency to synergism in cell lines with low or no MGMT expression. TTFields concurrent with both TMZ and CCNU further increased treatment efficacy. Mechanistically, TTFields elevated the levels of DNA double strand breaks and lowered expression of FA-BRCA pathway proteins, as detected by fluorescence microscopy and western blot, respectively. The involvement of the FA-BRCA pathway in repair of DNA damage induced by CCNU and the BRCAness state induced by TTFields rationalize the synergy seen for TTFields with CCNU, especially in cells absent of MGMT. The results suggest a potential benefit of TTFields therapy concomitant with TMZ/CCNU for the treatment of GBM.

RTID-05. TRIAL IN PROGRESS: DOSE-FINDING STUDY AND EVALUATION OF [177LU]LU-DOTA-TATE IN COMBINATION WITH STANDARD OF CARE IN NEWLY DIAGNOSED GLIOBLASTOMA AND AS A SINGLE AGENT IN RECURRENT GLIOBLASTOMA

Abstract Patients with glioblastoma have a poor prognosis despite extensive efforts to develop new treatments. Standard of care for newly diagnosed patients is surgery followed by radiotherapy plus temozolomide. However, temozolomide only provides a clinical benefit to patients who have glioblastomas with a methylated O(6)-methylguanine-DNA methyltransferase (MGMT) gene promotor. Disease recurrence is inevitable and subsequent treatments have poor outcomes due to limited efficacy and a lack of established therapeutic regimens. [68Ga]Ga-DOTA-TATE is a radioligand imaging agent that selectively binds to somatostatin receptors (SSTRs) and is used with positron emission tomography (PET) for the molecular imaging of SSTR-positive neuroendocrine tumors. Glioblastoma tumoral PET scans have shown moderate uptake of [68Ga]Ga-DOTA-TATE. The radioligand therapy [177Lu]Lu-DOTA-TATE has the same SSTR-targeted ligand and demonstrated promising clinical activity in a pilot study in patients with Grade III/IV gliomas. This Phase 1b open-label dose-finding study (NCT05109728) will determine the recommended [177Lu]Lu-DOTA-TATE dose in three different groups of glioblastoma (newly diagnosed with methylated MGMT promoter [group 1], newly diagnosed with unmethylated MGMT promoter [group 2], and recurrent disease [group 3]). All participants will be scanned with [68Ga]Ga-DOTA-TATE imaging during screening and, for each group, approximately 15 participants will be enrolled in consecutive cohorts of 3–6 participants. All participants will receive up to 6 administrations of [177Lu]Lu-DOTA-TATE (initial dose 150 mCi with 3 provisional dose levels up to 250 mCi) using the Bayesian Optimal Interval design. Group 1 will receive [177Lu]Lu-DOTA-TATE every 4 weeks with concomitant radiotherapy and temozolomide, followed by temozolomide maintenance. Group 2 will receive [177Lu]Lu-DOTA-TATE every 4 weeks for 3 doses with radiotherapy then every 3 weeks as a single agent. Group 3 will receive [177Lu]Lu-DOTA-TATE only, every 3 weeks. The primary endpoint is incidence of dose limiting toxicity. Secondary endpoints include overall objective status (modified RANO criteria), progression free survival, overall survival and safety.

434P Outcome of high grade glioma patients: A single institution experience

High Grade Glioma include all grade III/IV primary brain tumors of Astrocytic, oligodendroglial and mixed cellular lineage and are associated with poor prognosis. The standard of care for high grade glioma is concomitant chemoradiation and Temozolomide with median survival of 12-15 months in glioblastoma and 2-5 years with newly diagnosed anaplastic gliomas. Prognosis is poor with the median survival of 3-9 months at first recurrence which drops to few weeks for more than 90% of the patients at second or subsequent recurrence.

Comparison of Two Phase II Trials of Neoadjuvant Temozolomide Followed with Concomitant and Adjuvant Temozolomide and Hypofractionated Accelerated Radiotherapy with or without Metformin in Patients with Newly Diagnosed Glioblastoma

<h3>Purpose/Objective(s)</h3> Metformin (MTF) inhibits the proliferation of Glioblastoma (GBM) cells by activating adenosine monophosphate-activated protein kinase (AMPK), and mTOR, with subsequent sensitization to ionizing radiation and Temozolomide (TMZ). Furthermore, MTF reduces blood glucose levels and growth factors including insulin and insulin-growth factors. <h3>Materials/Methods</h3> Each trial consisted of 50 adults with newly diagnosed GBM. Within 4-5 weeks from surgery patients received either: (1) neo-adjuvant TMZ (75 mg/m²PO QD) for 2 weeks prior to Hypofractionated Accelerated Radiotherapy (HART) (60 Gy in 20 daily fractions over 4 weeks) given with concomitant and adjuvant TMZ given for 6 cycles at 150–200 mg/m² (N-HART) trial ClinicalTrials.gov NCT # NCT01702610; or (2) neo-adjuvant TMZ (75 mg/m²PO QD) + MTF (850 mg PO BID) for 2 weeks prior to HART with concomitant and adjuvant MTF + TMZ. Adjuvant TMZ + MTF were given for 6 cycles ClinicalTrials.gov NCT # 02780024. Survival analyses were done according to the Kaplan-Meier methods and Log-rank statistics. <h3>Results</h3> The median follow up for patients at risk was 107.9 months for the N-HARTT, and 34.3 months for the M-HARTT trials. The 2 cohorts were balanced for age and ECOG status. Gross total resection was performed in 54% of N-HARTT versus 84% in M-HARTT cohort. MGMT-gene promoter was methylated in 48% in N-HARTT trial compared to 32% in the M-HARTT trial. The median overall survival (OS) and PFS were 22.3 months, and 13.7 months, respectively for the N-HARTT trial compared with 29.5 months, and 13.7 months for the M-HARTT cohort [p=0.22 HR 0.91 (95% CI 0.56-1.47)]. Patients with unmethylated MGMT tumors had a median OS of 15 months in the N-HARTT trial compared to 24 months for patients with unmethylated MGMT tumors treated on the M-HARTT trial [(p=0.07 HR 0.64 (CI 95% 0.35-1.17)]. Patients with methylated MGMT tumors had 46.3 months median OS versus 50 months for patients with methylated MGMT tumors treated on N-HARTT and M-HARTT trials, respectively [(p=0.25 HR 1.37 (CI 95% 0.88-2.15)]. In a sub-group analysis of the M-HARTT trial, we observed that the median OS of patients with an average blood glucose levels of < 5 mmol/L has not been reached versus a median OS of 25.7 months for patients with blood glucose levels ≥ 5 mmol/L, (p=0·03 HR 0·30 95%CI, 0·13–0.67 Log-rank) <h3>Conclusion</h3> The addition of MTF in the M-HART trial resulted in an encouraging improvement of the median OS compared with N-HART trial. The main impact was observed in patients with unmethylated MGMT tumors. Furthermore, the results are suggestive for a potential role for glycemic control on outcomes.

A new approach to delineating clinical target volume for radiotherapy of glioblastoma: A phase II trial.

No consensus has currently been reached regarding the optimal radiation volume for radiotherapy of glioblastoma. Here, we have proposed a new delineation approach to delineating clinical target volume based on the relationship between the growth patterns of glioblastoma and neural pathways. Its safety and efficacy were evaluated in a phase II clinical trial. A total of 69 patients with histologically confirmed glioblastoma were enrolled. All patients underwent tumor resection, followed by focal radiotherapy and concomitant temozolomide (TMZ), and then received six cycles of adjuvant TMZ. The gross tumor volume (GTV) was defined as the surgical resection cavity plus any residual enhancing tumor, on contrast enhanced T1-weighted MRI. The clinical target volume (CTV) was delineated through our new approach. The median recurrence-free survival (RFS) and overall survival (OS) were 11.4 months and 18.2 months, which were better than the previous reports. Relapse was found in 47 patients, of whom 41 patients (87.2%) failed in central, two patients (4.3%) failed in field, and four patients (8.5%) failed in distance. No marginal recurrence was found. Our regimen showed a trend of lower rates of marginal recurrence, and the brain volume of high-dose radiation fields in our regimen was similar to that of EORTC (p = 0.257). We have proposed a novel method for the delineation of clinical target volume by referencing the nerve fiber bundles for radiotherapy of glioblastoma. The results of the present phase II clinical trial suggest that this approach may be feasible and effective.

Cranial Spinal Spreading of Canine Brain Gliomas after Hypofractionated Volumetric-Modulated Arc Radiotherapy and Concomitant Temozolomide Chemotherapy: A Four-Case Report.

Simple SummaryGliomas represent the second-most-common primary brain tumors in dogs. Surgery and radiotherapy are established treatment approaches with similar median survival time, whereas conventional chemotherapy is burdened by severe adverse effects. Spinal and leptomeningeal spread of gliomas have been described following radiotherapy treatment alone and the prognosis is generally inauspicious. In this work, a more aggressive radiotherapy protocol with concomitant radiosensitizing chemotherapy is represented but spinal-spread of the disease is reported, despite the fact that it was originally located exclusively in the brain area. This work suggests that the entire central nervous system should be investigated in diagnostic examinations and during the follow-up of canine gliomas. A radiotherapy dose-escalation trial and different chemotherapy dosages on a larger number of animals could estimate the optimal protocol to avoid spinal-spread while limiting radio-chemo toxicities. In the same context, prophylactic treatment to the spinal cord with a lower dose could also be the key to preventing recurrence across the cranial–spinal pathway and to improving quality of life.Gliomas are the second-most-common primary brain tumors in dogs. Surgery and radiotherapy are established treatment approaches with similar median survival time, whereas conventional chemotherapy is burdened by severe adverse effects. Spinal and leptomeningeal spread of gliomas have been described following radiotherapy treatment alone. The purpose of this study was to evaluate the outcome for four dogs with primary high-grade gliomas in the forebrain without evidence, at diagnosis, of neoplastic invasion along the spinal cord, that were treated with concomitant chemotherapy (temozolomide) and hypofractionated volumetric-modulated arc radiotherapy (VMAT-RT). Temozolomide was selected for its radiosensitive properties, and radiotherapy dose protocols of 37 Gy in 7 fractions or 42 Gy in 10 fractions were used. After an initial complete or partial response, tumors recurred across the cranial–spinal pathway. Post-mortem macroscopic examinations confirmed swollen spinal cord and hyperemic meningeal sleeve, with nodular lesions on the meningeal surface. Microscopically, infiltration of the spinal cord and meninges by neoplastic cells (with features of oligodendrogliomas) were observed. This work seems to suggest that the entire central nervous system should be investigated in diagnostic examinations of canine gliomas. Dose-escalation trials and/or spinal cord prophylaxis treatment could also be evaluated to prevent tumor progression.

CGAS-STING pathway targeted therapies and their applications in the treatment of high-grade glioma.

Median survival of patients with glioblastoma (GBM) treated with standard of care which consists of maximal safe resection of the contrast-enhancing portion of the tumor followed by radiation therapy with concomitant adjuvant temozolomide (TMZ) remains 15 months. The tumor microenvironment (TME) is known to contain immune suppressive myeloid cells with minimal effector T cell infiltration. Stimulator of interferon genes (STING) is an important activator of immune response and results in production of Type 1 interferon and antigen presentation by myeloid cells. This review will discuss important developments in STING agonists, potential biomarkers for STING response, and new combinatorial therapeutic approaches in gliomas.