Macdonald Criteria Research Articles

Alliance A071401: Phase II trial of abemaciclib in patients with grade 2/3 meningiomas harboring somatic NF2 or CDK pathway alterations.

2001 Background: Systemic treatments are limited for patients with meningiomas that have progressed after surgery and/or radiation. Loss of NF2and CDKN2A/Bare common in higher grade meningiomas and promote meningioma progression in preclinical models. We evaluated the efficacy of abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, as part of Alliance umbrella trial A071401, a genomically driven phase II study in recurrent or progressive meningiomas. Methods: Eligible patients (pts) with grade 2/3 tumors and NF2 mutations or CDK pathway alterations were treated with abemaciclib 200 mg orally twice daily until progressive disease. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR) by Macdonald criteria; the trial would be declared positive if either endpoint was met. Twenty-four evaluable pts provided >85% power to detect a PFS6 >41.5% (vs. null 15%; alpha =0.02). The threshold for promising results for PFS6 was 8+/24 pts. For RR, 24 evaluable pts provided >89% power to detect RR >20% (vs. null 2.5%; alpha = 0.021). The threshold for promising results for RR was 3+/24 pts. Results: Of 83 pts screened while the abemaciclib arm was open between September 15, 2021 and October 3, 2022, 36 eligible pts received treatment. The mean number of treatment cycles administered was 7 and median follow-up since start of treatment was 11 months. The first 24 pts that met eligibility criteria and began treatment were considered evaluable for the primary endpoint analysis. Of the 24 pts evaluated, 58% were female and the median age was 62 years. The observed PFS6 rate was 54% (13/24 pts, 95% confidence interval 33-75%), thus the study met PFS6 endpoint. No objective responses were observed. Of the 36 pts who started treatment, eight had a grade 3 and two had a grade 4 adverse event at least possibly related to treatment. Grade 3 toxicities included anemia (2), neutropenia (2), leukopenia (1), blurry vision (1), diarrhea (2), fatigue (2), ALT elevation (1), dehydration (1), hyperkalemia (1), hyponatremia (1), dizziness (1), acute kidney injury (1), and thromboembolic event (1). Grade 4 toxicities included ALT elevation (1), AST elevation (1) and vomiting (1). Conclusions: Abemaciclib was well tolerated and resulted in an improved PFS6. The overall trial endpoint was met. Abemaciclib warrants further investigation for the treatment of patients with progressive grade 2/3 meningiomas. Support: U10CA180821, U10CA180882; UG1CA189867 (NRG Oncology); Eli Lilly; https://acknowledgments.alliancefound.org . Clinical trial information: NCT02523014 .

RAPNO efforts in Brain Tumour Outcomes.

Assessing treatment efficacy for brain tumours has evolved since its inception with the introduction of MacDonald's criteria, which pioneered the utility of imaging to determine an objective and quantifiable response to treatment. This criterion failed to distinguish pseudo response or progression from progression and did not account for non-enhancing disease therefore; the response assessment in neuro-oncology (RANO) working group was established to account for these limitations. Since, its commencement it has worked to determine response assessment for multiple tumours. As paediatric tumours exhibit heterogeneous and variable-enhancing characteristics, the response assessment in paediatric neuro-oncology (RAPNO) working group was formed to create separate criteria. Six response criteria have been published to date, and the article summarizes them.

3D volume growth rate evaluation in the EORTC-BTG-1320 clinical trial for recurrent WHO grade 2 and 3 meningiomas.

We previously reported that tumor 3D volume growth rate (3DVGR) classification could help in the assessment of drug activity in patients with meningioma using 3 main classes and a total of 5 subclasses: class 1: decrease; 2: stabilization or severe slowdown; 3: progression. The EORTC-BTG-1320 clinical trial was a randomized phase II trial evaluating the efficacy of trabectedin for recurrent WHO 2 or 3 meningioma. Our objective was to evaluate the discriminative value of 3DVGR classification in the EORTC-BTG-1320. All patients with at least 1 available MRI before trial inclusion were included. 3D volume was evaluated on consecutive MRI until progression. 2D imaging response was centrally assessed by MRI modified Macdonald criteria. Clinical benefit was defined as neurological or functional status improvement or steroid decrease or discontinuation. Sixteen patients with a median age of 58.5 years were included. Best 3DVGR classes were: 1, 2A, 3A, and 3B in 2 (16.7%), 4 (33.3%), 2 (16.7%), and 4 (33.3%) patients, respectively. All patients with progression-free survival longer than 6 months had best 3DVGR class 1 or 2. 3DVGR classes 1 and 2 (combined) had a median overall survival of 34.7 months versus 7.2 months for class 3 (P = .061). All class 1 patients (2/2), 75% of class 2 patients (3/4), and only 10% of class 3 patients (1/10) had clinical benefit. Tumor 3DVGR classification may be helpful to identify early signals of treatment activity in meningioma clinical trials.

Assessing the impact of distortion correction on Gamma Knife radiosurgery for multiple metastasis: Volumetric and dosimetric analysis

IntroductionMagnetic resonance imaging (MRI) is a robust neuroimaging technique and is the preferred method for stereotactic radiosurgery (SRS) planning. However, MRI data always contain distortions caused by hardware and patient factors. Research questionCan these distortions potentially compromise the effectiveness and safety of SRS treatments? Material and methodsTwenty-six MR datasets with multiple metastatic brain tumors (METs) used for Gamma Knife radiosurgery (GKRS) were retrospectively evaluated. A commercially available software was used for distortion correction. Geometrical agreement between corrected and uncorrected tumor volumes was evaluated using MacDonald criteria, Euclidian distance, and Dice similarity coefficient (DSC). SRS plans were generated using uncorrected tumor volumes, which were assessed to determine their coverage of the corrected tumor volumes. ResultsThe median target volume was 0.38 cm3 (range,0.01–12.38 cm3). A maximum displacement of METs of up to 2.87 mm and a median displacement of 0.55 mm (range,0.1–2.87 mm) were noted. The median DSC between uncorrected and corrected MRI was 0.92, and the most concerning case had a DSC of 0.46. Although all plans met the optimization criterion of at least 98% of the uncorrected tumor volume (median 99.55%, range 98.1–100%) receiving at least 100% of the prescription dose, the percent of the corrected tumor volume receiving the total prescription dose was a median of 95.45% (range,23.1–99.5%). Discussion and conclusionMRI distortion, though visually subtle, has significant implications for SRS planning. Regular utilization of corrected MRI is recommended for SRS planning as distortion is sometimes enough to cause a volumetric miss of SRS targets.

Diffuse low-grade glioma: What is the optimal linear measure to assess tumor growth?

Radiological follow-up of diffuse low-grade gliomas (LGGs) growth is challenging. Approximative visual assessment still predominates over objective quantification due to the complexity of the pathology. The infiltrating character, diffuse borders and presence of surgical cavities demand LGG-based linear measurement rules to efficiently and precisely assess LGG evolution over time. We compared optimized 1D, 2D, and 3D linear measurements with manual volume segmentation as a reference to assess LGG tumor growth in 36 patients with LGG (340 magnetic resonance imaging scans), using the clinically important mean tumor diameter (MTD) and the velocity diameter expansion (VDE). LGG-specific progression thresholds were established using the high-grade gliomas-based RECIST, Macdonald, and RANO criteria, comparing the sensitivity to identify progression/non-progression for each linear method compared to the ground truth established by the manual segmentation. 3D linear volume approximation correlated strongly with manually segmented volume. It also showed the highest sensitivity for progression detection. The MTD showed a comparable result, whereas the VDE highlighted that caution is warranted in the case of small tumors with multiple residues. Novel LGG-specific progression thresholds, or the critical change in estimated tumor volume, were increased for the 3D (from 40% to 52%) and 2D methods (from 25% to 33%) and decreased for the 1D method (from 20% to 16%). Using the 3D method allowed a ~5-minute time gain. While manual volumetric assessment remains the gold standard for calculating growth rate, the 3D linear method is the best time-efficient standardized alternative for radiological evaluation of LGGs in routine use.

RADT-37. INTERIM RESULTS OF ACCELERATOR-BASED BORON NEUTRON CAPTURE THERAPY, RANDOMIZED CONTROLLED TRIAL FOR RECURRENT AND REFRACTORY HIGH-GRADE MENINGIOMAS

Abstract BACKGROUND High-grade meningiomas (HGMs) recurred after X-ray treatment showed 5.2 months as median progression free survival (mPFS) and only 24.6 months as median overall survival (mOS) from the literatures. Recently, we showed much more excellent OS and PFS using reactor-based boron neutron capture therapy (BNCT) (Neuro-Oncology 24:90-98, 2022). Based on these data, we started “A phase II investigator-lead RCT using accelerator-based BNCT system for refractory recurrent high-grade meningioma”, with the aid of Japanese governmental financial support. METHODS We prepared 2 study arms, BNCT test treatment arm (12 subjects) and control best supportive care arm (6 subjects) in RCT fashion. PFS judged by third party committee was set-up as primary endpoint and PFS judged by investigators themselves and OS of BNCT arm were set-up as secondary endpoints. To diminish ethical problems of this RCT, rescue BNCT is permitted for control group patients, if they showed progress disease during the observation period. Macdonald criteria was adopted for assessment. The first patient-in was August 2019 and the last patient-in was August 2021. Interim results of this trial: Three and two grade 3 subjects were included in BNCT and control arm, respectively. Others were grade 2 subjects. As of April 20, 2023, mPFS judged by investigators showed 90 weeks and 8 weeks for BNCT and control arm, respectively (P = 0.0004). OS-2 year rates of BNCT and control arms are 91.7% and 25%, respectively (p = 0.01) CONCLUSION Primary endpoint, mPFS judged by third party committee is still being closed and unknown, so far, until the end of the trial (August 2024). With regard to secondary endpoints, there are marked differences in both arms in mPFS judged by investigators. Also, OS in BNCT arm is extremely excellent in comparison with EORTC RCT of “trabectedine” and PD-1 blockade reports, just recently appeared.

Прогнозування перебігу розсіяного склерозу на підставі клінічних особливостей дебюту у пацієнтів Полтавської області

The purpose of the study was to demonstrate the importance of studying variants of the debut of multiple sclerosis, to reveal the dependence of the rate of progression on the clinical picture of the debut of multiple sclerosis by examining patients and retrospective analysis of clinical data. Materials and methods. The study analyzed 60 cases of relapsing-remitting and secondary-progressive multiple sclerosis in patients who were undergoing inpatient treatment in the neurological department of the communal enterprise “M. V. Sklifosovskyi Poltava Regional Clinical Hospital of the Poltava Regional Council” from 2019 to 2021. Complaints, anamnestic data, results of a complex clinical and neurological examination of patients with multiple sclerosis at the onset and throughout the course of the disease were studied. The diagnosis was established according to Mac-Donald criteria. The severity of clinical manifestations was assessed using the Extended Disability Scale. Results and discussion. The rate of disease progression was assessed retrospectively. The ratio of the number of the Extended Disability Scale points at this moment to the duration of the disease in years was studied. In the group of patients with a monosymptomatic debut, the rate of progression was: 0.64 in women, 1.2 in men. In patients with an acute polysymptomatic onset, the values of the rate of progression were 0.7 and 2.1, respectively. As a result of the retrospective analysis, several options for the onset of multiple sclerosis were identified: monosymptomatic, polysymptomatic, patients with a radiologically isolated syndrome, and patients with a characteristic clinical picture, but without pathological changes on magnetic resonance imaging. One of the most frequent clinical manifestations of the debut in patients in the Poltava region was sensitive disorders. It is worth noting that special attention should be paid to the study of vibration sensitivity. When collecting anamnestic data, it is necessary to clarify the presence of Lhermitte syndrome. The rate of progression of multiple sclerosis was found to be higher in male patients with polysymptomatic onset and motor disturbances, between the first symptoms (patient complaints) and the diagnosis of multiple sclerosis from 3 months to several years. Conclusion. The presented research results can be useful for neurologists, general practitioners, radiologists and doctors of other specialties for early diagnosis, prescribing pathogenetic treatment of multiple sclerosis and predicting its course. Prospects for further research are related to the monitoring of clinical observations of multiple sclerosis with the aim of improving diagnostic, therapeutic and rehabilitation measures

RTID-06. A RANDOMIZED CONTROLLED TRIAL USING ACCELERATOR-BASED BNCT SYSTEM FOR REFRACTORY RECURRENT HIGH-GRADE MENINGIOMA

Abstract BACKGROUNDS Recently, nuclear reactors have been replaced with accelerator-based neutron sources (ABNS) for boron neutron capture therapy (BNCT). High-grade meningiomas (HGM) are refractory, especially recurred after some radiotherapy. We are now applying randomized controlled trial (RCT) of “A phase II clinical trial using accelerator-based BNCT system for refractory recurrent high-grade meningioma”. STUDY DESIGN PMDA in Japan which is a counter part of FDA in USA suggested the importance of RCT even for this exploratory clinical trial for HGM. Along to this suggestion, we prepared 2 study groups, BNCT test treatment group and control best supportive care (BSC) group. Progression free survival (PFS) was set-up as primary endpoint. Rescue BNCT is allowed for control group patients, if they showed progress disease (PD) during observation. Two-dimensional modified Macdonald criteria is adopted for assessment. METHODS The trial started in August 2019. Eighteen subjects were enrolled and divided in 12 and 6 subjects for BNCT and control BSC group, respectively. Cyclotron-based ABNS system was used for neutron source. Neutron-irradiation time is determined not to exceed to 7.5 Gy-Eq for scalp dose which was referencing preceding phase I trial for malignant gliomas. The last patient-in was August 2021. INTERIM RESULTS (as of April 30, 2022): All 6 cases of control group were judges as PD. Seven out of 11 cases of BNCT group were judged as PD. One case of BNCT group dropped out from the study with withdrawal of consent. Median PFS were 8 and 64 weeks for control group and BNCT group, respectively. Log-rank test showed marked statistical difference with p-value of 0.000401 between these 2 groups. CONCLUSIONS This RCT showed a marked difference of PFS between accelerator-based BNCT group and control group, so far. We will keep on observation at least next 2 years for other endpoints.

An algorithm to determine the date when the McDonald criteria are met for the diagnosis of relapsing-remitting multiple sclerosis

BackgroundA patient is diagnosed with multiple sclerosis once they meet the McDonald criteria of dissemination in space and time. Studies of cohorts of patients with multiple sclerosis need a reproducible way to determine an accurate date of diagnosis. We developed an automatic data-driven algorithm to determine the date when the MacDonald criteria are met, which we validated with the Registre Lorrain des Scleroses en Plaques (ReLSEP), a regional French registry of patients with multiple sclerosis. MethodsWe developed an algorithm to determine the date of diagnosis based on clinical and paraclinical data adapted from the four versions of the McDonald criteria. For validation, the dates of diagnosis generated by the algorithm were compared with those determined by an expert physician using the patients’ files as the gold standard. We calculated the sensitivity and specificity of the algorithm to provide a date, then we tested the equivalence between the dates of the gold standard and the algorithm (two-one-sided-t-test). ResultsThe algorithm used every possibility of determining dissemination in space and time according to the four sets. The sensitivity of the algorithm was 100% for the four sets, and specificity ranged between 95 and 100%. The difference between the dates of diagnosis found by the physician and the algorithm was usually less than 2 weeks (equivalence test P<0.0001). ConclusionThe algorithm appears to be an efficient surrogate to accurately determine dates of diagnosis of multiple sclerosis in datasets of patients.

The interim result of a phase I/II study of nivolumab with or without ipilimumab in combination with multi-fraction stereotactic radiosurgery for recurrent, high-grade, radiation-relapsed meningioma.

2068 Background: There is a lack of effective therapy for recurrent high-grade meningiomas who relapsed after prior radiation therapy (RT). ETCTN 10186 is a phase I/II study to evaluate the feasibility and preliminary clinical efficacy of combining reirradiation using fractionated radiosurgery with nivolumab plus or minus ipilimumab for recurrent high-grade meningiomas. The preliminary results from the phase I portion are reported here. Methods: Recurrent grade II-III meningioma patients were treated with radiosurgery plus nivolumab with or without ipilimumab. Key eligibility criteria include age ≥ 18 years; ECOG score ≤ 2; tumor diameter 1-5 cm; prior radiation dose ≤ 70 Gy; normal organ function; no active autoimmunity. During the phase I portion, eligible patients were treated according to treatment-escalation schema following the modified 3+3 design (Table 1). The maximum tolerated combination (MTC) will be the regimen at which ≤ 1/6 patients experience dose-limiting toxicity (DLT) within 8 weeks of the start of study therapy. During the phase II portion, a total of 24 evaluable patients will be enrolled at the MTC using Simon’s MiniMax two-stage design. The primary endpoint of the phase I portion is to determine the MTC. Objective radiological responses (ORRs) are defined as per the Macdonald criteria. One cycle of immunotherapy is defined as 4 weeks of nivolumab with or without concurrent ipilimumab. Results: From 7/2019 to 3/2021, 13 patients were enrolled in the phase I, including 6 with regimen A and 7 with regimen B (Table). The median prior RT dose was 56 Gy (18-70) at a median interval of 2.8 years (1.3-13.3). There was no DLT in either cohort, so regimen B was deemed the MTC. The median cycles of immunotherapy completed were not significantly different between cohort A and B (11 vs. 6, p = 0.41, respectively). Three cohort A patients and 2 cohort B patients completed all planned doses of immunotherapy. Most patients stopped due to progression, and only one cohort B patient stopped due to treatment-related toxicity (grade 3 hypophysitis and encephalitis after 6 cycles of immunotherapy). After a median follow-up of 11.1 months, there have been 5 progressions and 4 deaths. The 6 month-PFS and 12 month-PFS rates are 62% and 54%, respectively. Two ORRs have been reported by institutional assessment, and central radiology review is ongoing and will be reported. Conclusions: Reirradiation using fractionated radiosurgery with nivolumab plus or minus ipilimumab are well tolerated for radiation-relapsed high-grade meningiomas. Phase II study of regimen B is currently enrolling. Clinical trial information: NCT03604978. [Table: see text]

MRI Response Assessment in Glioblastoma Patients Treated with Dendritic-Cell-Based Immunotherapy.

Simple SummaryIn order to compare responses to different therapies among clinical trials and to differentiate between therapy-induced changes and true tumor progression, reliable response parameters are crucial. With the advent of targeted and immunologic treatments, several assessment tools have been proposed. In this post hoc analysis we compared assessment criteria according to MacDonald, RANO, mRANO, iRANO as well as Vol-RANO and Vol-mRANO in patients with newly diagnosed glioblastoma treated with standard of care (SOC) ± tumor lysate-charged autologous dendritic cells (Audencel). We found that the best correlation between progression-free survival (PFS) and overall survival (OS) was seen for mRANO and Vol-mRANO. Interestingly, iRANO was not superior for predicting OS in patients treated with Audencel.Introduction: In this post hoc analysis we compared various response-assessment criteria in newly diagnosed glioblastoma (GB) patients treated with tumor lysate-charged autologous dendritic cells (Audencel) and determined the differences in prediction of progression-free survival (PFS) and overall survival (OS). Methods: 76 patients enrolled in a multicenter phase II trial receiving standard of care (SOC, n = 40) or SOC + Audencel vaccine (n = 36) were included. MRI scans were evaluated using MacDonald, RANO, Vol-RANO, mRANO, Vol-mRANO and iRANO criteria. Tumor volumes (T1 contrast-enhancing as well as T2/FLAIR volumes) were calculated by semiautomatic segmentation. The Kruskal-Wallis-test was used to detect differences in PFS among the assessment criteria; for correlation analysis the Spearman test was used. Results: There was a significant difference in median PFS between mRANO (8.6 months) and Vol-mRANO (8.6 months) compared to MacDonald (4.0 months), RANO (4.2 months) and Vol-RANO (5.4 months). For the vaccination arm, median PFS by iRANO was 6.2 months. There was no difference in PFS between SOC and SOC + Audencel. The best correlation between PFS/OS was detected for mRANO (r = 0.65) and Vol-mRANO (r = 0.69, each p < 0.001). A total of 16/76 patients developed a pure T2/FLAIR progressing disease, and 4/36 patients treated with Audencel developed pseudoprogression. Conclusion: When comparing different response-assessment criteria in GB patients treated with dendritic cell-based immunotherapy, the best correlation between PFS and OS was observed for mRANO and Vol-mRANO. Interestingly, iRANO was not superior for predicting OS in patients treated with Audencel.

Circulatory antioxidant and oxidative stress markers are in correlation with demographics but not cognitive functions in multiple sclerosis patients

BackgroundMultiple sclerosis (MS) is the most common non-traumatic cause of disability in younger adults. MS can be presented with a wide range of symptoms such as cognitive impairment (CI). Oxidative stress (OXS) is a major basis of the pathogenesis of MS. There is a positive correlation between OXS factors and the progression of the disease in MS patients. There are limited studies regarding the role of OXS in MS-related CI. In this study, as an exploratory analysis, we assess the role of endogenous antioxidants and OXS factors in cognitive function, the severity of disability due to MS, and demographic findings in a sample of MS patients. MethodsAdult (>18 years old) patients with a definite diagnosis of MS based on 2017 revised MacDonald criteria were included in this study. The neurophysiological assessment was conducted, using the validated Persian version of minimal assessment of cognitive function in multiple sclerosis (MACFIMS) battery, which is composed of seven different tests. Based on the structure of the battery, CI was defined as a failure in at least two different components of the MACFIMS battery. The patients were separated into two groups of CI and non-CI. Examined antioxidant factors included catalase Activity (CAT), Glutathione Peroxidase 1 (GPX1), Glutathione Peroxidase 2 (GPX2), Reduced Glutathione (GSH), Superoxide Dismutase (SOD), and serum total antioxidant capacity (TAC). Malondialdehyde (MDA) was also measured as an OXS marker. Results71 patients were involved in this study. The type of MS was relapsing-remitting MS (RRMS) in 80.28% of the participants. Disease duration (P<0.01), type of MS (p<0.01), and EDSS score (p<0.01) were different between CI and non-CI groups, but there were not any significant differences in CAT (p = 0.80), GPX1 (p = 0.71), GPX2 (p = 0.41), GSH (p = 0.96), TAC (p = 0.13), SOD (p = 0.37), and MDA (p = 0.82). A significant difference between RRMS and progressive MS (PMS) patients in the levels of GPX1 (p = 0.01), GPX2 (p = 0.01), and SOD (p = 0.01) was observed. Also, we found higher circulatory levels of CAT (p = 0.02) and TAC (p<0.01) in male MS patients. We found significant correlations between aging and CAT (R = 0.28; p = 0.01), GPX1 (R = 0.36; p<0.01), GPX2 (R = 0.34; p<0.01), and SOD (R = 0.40; p<0.01). EDSS, the duration of the disease, relapse rate, and the number of impaired cognitive tasks were not correlated with any of investigated OXS or antioxidant factors (p>0.05). In terms of a detailed investigation of associations between MACFIMS battery components and levels of OXS and antioxidant factors, there were no significant relations in this regard (p>0.05). Based on the logistic regression multivariate analysis, only disease duration (p = 0.03) and GPX1 (p = 0.01) were independently associated with CI in MS patients in our sample. ConclusionThe circulatory levels of GPX1, GPX2, and SOD are significantly different between RRMS and PMS patients. Neither endogenous antioxidants nor MDA, as an OXS biomarker, are associated with the cognitive function or level of physical disability in MS patients. Limitations of this study suggest a need for future studies in a larger sample of MS patients.

Differential diagnosis of multiple sclerosis

Background and objectivesDespite immense progress of imaging and updates in the MacDonald criteria, the diagnosis of multiple sclerosis remains difficult as it must integrate history, clinical presentation, biological markers, and imaging. There is a multitude of syndromes resembling multiple sclerosis both clinically or on imaging. The goal of this review is to help clinicians orient themselves in these various diagnoses. We organized our review in two categories: inflammatory and autoimmune diseases that are close or can be confused with multiple sclerosis, and non-inflammatory syndromes that can present with symptoms or imaging mimicking those of multiple sclerosis. MethodReview of literature ConclusionProgress of imaging and biological sciences have drastically changed the approach and management of multiple sclerosis. But these developments have also shined a light on a variety of diseases previously unknown or poorly known, therefore greatly expanding the differential diagnosis of multiple sclerosis. While autoimmune, many of these diseases have underlying biological mechanisms that are very different from those of multiple sclerosis, rendering MS therapies usually inefficient. It is crucial to approach these diseases with utmost thoroughness, integrating history, clinical exam, and evolving ancillary tests.

CTNI-56. A PHASE II CLINICAL TRIAL USING ACCELERATOR-BASED BNCT SYSTEM FOR REFRACTORY RECURRENT HIGH-GRADE MENINGIOMA

Abstract BACKGROUND Boron neutron capture therapy (BNCT) is tumor-selective particle radiation. Recently accelerator-based neutron sources (ABNS) have been developed for clinical trials to obtain on-label use, i.e. new drug approval for malignant gliomas. Recently Japanese regulatory authority has just given this permission for H&amp;N cancers. Recurrent high-grade meningiomas (HGM) are difficult to control. We have applied reactor-based BNCT for 46 cases of refractory HGM. All cases showed good tumor shrinkage with good local control. PURPOSES Based on these situations, we proposed “A phase II clinical trial using accelerator-based BNCT system for refractory recurrent HGM” for AMED in Japan which is similar to NIH in USA. This proposal was successfully accepted. DESIGN We prepared 2 study groups, BNCT test treatment group and control best supportive care group, for RCT. PFS and OS were set-up as primary and secondary endpoints, respectively. Rescue BNCT is allowed for control group patients, if they showed PD during observation. Modified Macdonald criteria is adopted for assessment. Hypothesized PFS of treatment group and control group was 5 months and 24 months, respectively. The trial started in August 2019. METHODS Twelve BNCT and 6 control subjects will be included. Patients’ eligibility criteria is recurrent HGM after some radiotherapy. Cyclotron-based ABNS system is used for neutron source. Neutron-irradiation time is determined not to exceed to 7.5 Gy-Eq for scalp dose which was referencing preceding phase I trial for malignant gliomas. PROGRESS As of April 2020, 4 subjects were included, 3 for BNCT treatment group, 1 for control best supportive care group. The control subject showed PD during one month observation and rescue treatment showed PR. Treatment group 3 cases showed more than SD. CONCLUSION We started this RCT and will introduce the interim report of this clinical trial in the meeting.

Clinical Outcomes And Radiologic Response Of Incompletely Resected Grade 2-3 Meningiomas Treated With External Beam Radiation Therapy

To evaluate the clinical outcomes of incompletely resected grade 2-3 meningiomas treated with definitive external beam radiation therapy (EBRT). Grade 2 or 3 meningioma patients with measurable disease (≥1cm on MRI) who received EBRT after subtotal resection (STR) or biopsy at a tertiary cancer center were retrospectively reviewed. Radiologic response was evaluated using the MacDonald criteria. Local control (LC), progression-free survival (PFS), and overall survival (OS) rates were estimated using the Kaplan-Meier method. Cox regression analysis was performed to identify factors associated with improved LC. Twenty-eight patients with grade 2 (n = 24) or grade 3 (n = 4) meningioma were irradiated from 2003 to 2018 after either STR (86%) or biopsy (14%). The median residual disease was 2.4 cm (range: 1.2-10.5), with a median bi-dimensional product of 3.6 cm2 (range: 1.3-57.4). EBRT included intensity-modulated radiation therapy (IMRT, 68%), proton beam therapy (PBT, 18%), or a combination of both (14%), to a median dose of 59.4 Gy (range: 50.4-63). After a median follow-up of 29 months, the 3-year LC, PFS and OS rates were 60%, 47%, and 68%, respectively. Response rate was 21% (6 partial responses), but 61% had any degree of radiographic shrinkage. The median time to partial response was 11 months (range: 5-13). Grade 2 (p = .049), smaller residual disease as estimated by bi-dimensional product (p = .027), and any radiographic shrinkage (p = .035) were associated with improved LC, but not radiation dose, use of PBT, nor objective response by the MacDonald criteria. Symptomatic radionecrosis occurred in 14% of cases. Clinical outcomes of incompletely resected grade 2-3 meningiomas remain limited despite high-dose EBRT; thus, additional novel therapy to combine with EBRT should be investigated. Radiologic response using the MacDonald criteria may not predict for LC and may not be the optimal criteria for response evaluation.

Alliance A071401: Phase II trial of FAK inhibition in meningiomas with somatic NF2 mutations.

2502 Background: Patients with progressive or recurrent meningiomas have limited treatment options. Clinical trials of systemic therapies for meningiomas have failed to demonstrate benefit. FAK inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically-driven phase II study in recurrent or progressive grade I-III meningiomas. Methods: Eligible patients (pts) whose tumors screened positively for NF2 mutations were treated with GSK2256098 750mg po bid until progressive disease in 2 separate cohorts: grade I or II/III meningiomas. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR) by Macdonald criteria; per study design, the trial would be declared positive if either endpoint was met. RR was evaluated across the overall cohort; PFS6 was evaluated within each subgroup. Historical benchmark data was obtained from Kaley et al. Neuro Oncol 2014. In the grade I group, 12 evaluable pts provided &gt;79% power to detect a PFS6 rate &gt;65% (vs. null hypothesis of 25%; alpha=0.014). In the grade II/III group, 24 evaluable pts provided &gt;85% power to detect a PFS6 &gt;41.5% (vs. null 15%; alpha=0.02). The threshold for promising results for PFS6 was: 7+/12(grade I) and 8+/24(grade II/III) pts. For RR, 36 evaluable pts provided &gt;94% power to detect RR &gt;20% (vs. null 2.5%; alpha= 0.012). Results: Of 322 pts screened for all mutation cohorts of the study, 36 eligible and evaluable pts with NF2 mutations were enrolled. Across all grades, one pt had a partial response and 24 had stable disease as best response to treatment. In Grade I pts, the observed PFS6 rate was 83% (10/12 pts; 95% CI: 52-98%). In Grade II/III pts, the observed PFS6 rate was 33% (8/24 pts; 95% CI: 16-55%). The study met PFS6 efficacy endpoint both for the Grade I and the Grade II/III cohorts. Treatment was well tolerated. Only 7 patients had a maximum grade-3 adverse event that was at least possibly related to treatment; toxicities across these pts included: proteinuria (2), rash (1), pain (1), ALT (1), AST (1), cholecystitis (1), hypertriglyceridemia (1), apraxia (1), and lymphopenia (1) with no grade 4 or 5 events. Conclusions: GSK2256098 had excellent tolerability andresulted in an improved PFS6 rate in pts with recurrent or progressive NF2-mutated meningiomas. Trial endpoint was met. FAK inhibition warrants further evaluation in this patient population. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org Clinical trial information: NCT02523014 .

ACTR-32. NRG ONCOLOGY RTOG 1205: RANDOMIZED PHASE II TRIAL OF CONCURRENT BEVACIZUMAB AND RE-IRRADIATION VS. BEVACIZUMAB ALONE AS TREATMENT FOR RECURRENT GLIOBLASTOMA

Abstract This study sought to determine whether re-irradiation (ReRT) and concurrent bevacizumab (BEV) improves overall survival (OS) compared to BEV alone in recurrent glioblastoma (GBM). Patients (pts) were randomized 1:1 to ReRT (35 Gy/10 fractions) plus BEV (IV 10 mg/kg q2 wks) vs. BEV alone. With 160 pts, there was 80% power to detect a 31% reduction in death hazard for BEV+RT at a one-sided significance level of 0.10 using a log rank test. OS and PFS were estimated by Kaplan-Meier and HRs estimated by exact binomial distribution. Objective response was assessed using MacDonald and RANO criteria. From 11/2012 to 4/2016, 182 pts were randomized, with 170 eligible, analyzable pts. 11 pts did not receive protocol treatment. Patient characteristics (age, KPS, re-resection rates) were balanced between arms. Median f/u for censored pts was 12.8 months (mos; min-max, 0.03–52.8). BEV+ReRT did not improve OS vs BEV alone, with median OS of 10.1 vs 9.7 mos, (HR=0.98, 95% CI=0.70–1.38, p=0.46). Median PFS for BEV+RT and BEV was 7.1 vs. 3.8 mos, respectively (HR=0.73, 95% CI=0.53–1.0, p=0.051). BEV+ReRT improved 6-mo PFS rate (PFS6): 54 vs. 29%, (HR=0.42, 95% CI=0.34–0.5, p=0.001). Overall, treatment was well tolerated: 5% acute and 0% delayed grade 3+ treatment-related AE. Most patients died from recurrent GBM. CONCLUSION: RTOG 1205 is the first, prospective, randomized multi-institutional study to evaluate the safety and efficacy of ReRT in recurrent GBM using modern RT techniques. Overall, ReRT was shown to be safe and well tolerated. BEV+ReRT did not demonstrate a benefit in OS but an improved PFS6, and clinically meaningful PFS improvement. Molecular correlates of response analyses are ongoing. Funded by U10CA180868, U10CA180822 from the National Cancer Institute.

510TiP - Phase I/II study of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, as a single agent and combined with chemotherapy, in patients with refractory haematological malignancies or solid tumours

Background9-ING-41 is a first-in-class, intravenously (IV) administered, small molecule potent selective GSK-3β inhibitor with significant pre-clinical antitumor activity in a broad spectrum of malignancies, both as a single agent and in combination with cytotoxic agents. GSK-3β is a serine/threonine kinase important in tumor progression and modulation of oncogenes, cell cycle regulators and mediators of epithelial-mesenchymal transition. Aberrant overexpression of GSK-3β is associated with advanced stage and aggressive tumor growth as well as chemotherapy resistance. Trial designThis Phase 1/2 study is designed to evaluate the safety and efficacy of 9-ING-41 as a single agent and in combination with cytotoxic agents, in patients with refractory cancers. Treatment consists of twice-weekly IV infusion of 9-ING-41 as a single agent (21-day-cycle) or combined with chemotherapeutic agents including gemcitabine, doxorubicin, lomustine, carboplatin, nab-paclitaxel, or paclitaxel. Study parts 1 and 2 will evaluate the safety and tolerability, describe any dose-limiting toxicity (DLT), determine the maximum tolerated dose (MTD) and the recommended Phase 2 study dose (RP2D) for 9-ING-41 as monotherapy (Part 1) and in combination with chemotherapies (Part 2). Part 3 (Simon 2-Stage Phase 2 at the RP2D) will assess clinical benefit in patients with relapsed or refractory malignancies treated with 9-ING-41-based combinations at the RP2D established in Part 2. Safety will be assessed by recording and monitoring adverse events (CTCAE). For solid tumors, response will be defined by response evaluation criteria in solid tumors (RECIST) 1.1 criteria in the evaluable lesion(s). For lymphoma, response will be assessed per the International Working Group Response Criteria. For CNS tumors, response will be followed by the RANO and the MacDonald criteria. The study is opening in 25 sites globally and will accrue approximately 250 patients. Clinical trial identificationNCT03678883. Legal entity responsible for the studyActuate Therapeutics Inc. FundingActuate Therapeutics Inc. DisclosureB. Carneiro: Research grant / Funding (institution): Actuate Therapeutics Inc; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer. L. Cavalcante: Research grant / Funding (institution): Actuate Therapeutics Inc. P. Munster: Research grant / Funding (institution): Actuate Therapeutics Inc. F. Giles: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Actuate Therapeutics Inc. All other authors have declared no conflicts of interest.

MLTI-02. A PHASE I TRIAL OF SORAFENIB WITH WHOLE BRAIN RADIOTHERAPY (WBRT) IN BREAST CANCER PATIENTS WITH BRAIN METASTASES AND A CORRELATIVE FLT-PET BRAIN IMAGING STUDY IN PATIENTS RECEIVING WBRT +/- SORAFENIB

BACKGROUND: Sorafenib has demonstrated anti-tumor efficacy in breast cancer and radiosensitizing activity preclinically. [18F] 3’deoxy-3’-fluorothymidine (FLT) is a PET tracer which correlates with cellular proliferation and may improve response assessment. METHODS: A phase I trial of whole brain radiotherapy (WBRT)+sorafenib was conducted using a 3 + 3 design. Sorafenib was given daily at the start of WBRT for 21 days (dose levels: 200mg, 400mg, and 600mg). The primary endpoints were to determine a maximum tolerated dose (MTD) and to evaluate safety and toxicity. The secondary endpoint was CNS progression-free survival (CNS-PFS). Macdonald Criteria were used for response assessment. A correlative serial FLT-PET imaging study was conducted to assess radiographic changes among pts receiving WBRT +/- sorafenib, in parallel with MRI. RESULTS:13 pts in the dose escalation were evaluable for dose-limiting toxicity (DLT). DLTs were: Grade (G) 4 increased lipase at 200mg (1 pt) and G3 rash at 400mg (3 pts) level. MTD was 200mg. Six additional pts were treated in an expansion cohort without additional DLT. 14 pts were evaluable for response. The overall response rate was 71%: 4 complete + 6 partial responses. Median follow up was 14 months (range: 3–44). Median CNS-PFS was 12.8 months (95%CI: 6.7-NR). A total of 15 pts (10 WBRT+sorafenib and 5 WBRT) were enrolled in the FLT-PET study: all had baseline FLT-PET, 14 with follow up at 7–10 days post WBRT (FU1), and 9 with followup at 12 weeks post WBRT (FU2). 55 baseline lesions were observed and analyzed: 38 at FU1 and 15 at FU2. Decline in average SUVmax of ≥25% was seen in 9/10 (90%) of WBRT+sorafenib pts and 2/4 (50%) of WBRT only pts at FU1. CONCLUSIONS: Concurrent WBRT+sorafenib appears safe at 200mg daily dose with clinical activity. This combination should be considered for further efficacy evaluation. NCT01724606 and NCT01621906.

The Neurologic Assessment in Neuro-Oncology (NANO) Scale as an Assessment Tool for Survival in Patients With Primary Glioblastoma.

The Neurologic Assessment in Neuro-Oncology (NANO) scale is a standardized objective metric designed to measure neurological function in neuro-oncology. Current neuroradiological evaluation guidelines fail to use specific clinical criteria for progression. To determine if the NANO scale was a reliable assessment tool in glioblastoma (GBM) patients and whether it correlated to survival. Our group performed a retrospective review of all patients with newly diagnosed GBM from January 1, 2010, through December 31, 2012, at our institution. We applied the NANO scale, Karnofsky performance score (KPS), Eastern Cooperative Oncology Group (ECOG) scale, Macdonald criteria, and the Response Assessment in Neuro-Oncology (RANO) criteria to patients at the time of diagnosis as well as at 3, 6, and 12 mo. Initial NANO score was correlated with overall survival at time of presentation. NANO progression was correlated with decreased survival in patients at 6 and 12 mo. A decrease in KPS was associated with survival at 3 and 6 mo, an increase in ECOG score was associated only at 3 mo, and radiological evaluation (RANO and Macdonald) was correlated at 3 and 6 mo. Only the NANO scale was associated with patient survival at 1 yr. NANO progression was the only metric that was linked to decreased overall survival when compared to RANO and Macdonald at 6 and 12 mo. The NANO scale is specific to neuro-oncology and can be used to assess patients with glioma. This retrospective analysis demonstrates the usefulness of the NANO scale in glioblastoma.