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BackgroundTemozolomide offers minimal benefit in patients with glioblastoma with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status, hence, the need for novel therapies. This study evaluated whether veliparib, a brain-penetrant poly(ADP-ribose) polymerase (PARP) inhibitor, acts synergistically with radiation and temozolomide.MethodsVERTU was a multicenter 2:1 randomized phase II trial in patients with newly diagnosed glioblastoma and MGMT-unmethylated promotor status. The experimental arm consisted of veliparib and radiotherapy, followed by adjuvant veliparib and temozolomide. The standard arm consisted of concurrent temozolomide and radiotherapy, followed by adjuvant temozolomide. The primary objective was to extend the progression-free survival rate at six months (PFS-6m) in the experimental arm.ResultsA total of 125 participants were enrolled, with 84 in the experimental arm and 41 in the standard arm. The median age was 61 years, 70% were male, 59% had Eastern Cooperative Oncology Group (ECOG) performance status of 0, and 87% underwent macroscopic resection. PFS-6m was 46% (95% confidence interval [CI]: 36%-57%) in the experimental arm and 31% (95% CI: 18%-46%) in the standard arm. Median overall survival was 12.7 months (95% CI: 11.4-14.5 months) in the experimental arm and 12.8 months (95% CI: 9.5-15.8 months) in the standard arm. The most common grade 3-4 adverse events were thrombocytopenia and neutropenia, with no new safety signals.ConclusionThe veliparib-containing regimen was feasible and well tolerated. However, there was insufficient evidence of clinical benefit in this population. Further information from correlative translational work and other trials of PARP inhibitors in glioblastoma are still awaited.

Information about invasive species needs to be spread rapidly across a wide geographic area following an invasion. However, in-person events can be time-consuming and costly for the participants, organizers, and presenters. Online programming like webinars can bridge this gap, but there is limited published data on how best to run these programs. We report on a 10-yr webinar program, Emerald Ash Borer University, and offer suggestions for improving their effectiveness as a communication tool. Webinar participants viewed the webinars positively and undertook recommended management actions. In addition, most of our survey respondents extended the reach of this program by widely sharing the information from the webinars. Posting the webinars on popular streaming platforms greatly extended their reach long after the live viewing event. Despite their longevity, viewers of recorded videos watched them differently than those viewing live events. We suggest modifying the format of future webinar presentations to accommodate these differences to improve information transfer.

BACKGROUND Grade 2 and 3 (G2/3) gliomas are the second largest group of brain tumors in adults. Although the prognosis for G2/3 gliomas at the time of relapse mirror those of glioblastoma, there are few trials in this space. METHODS LUMOS was a national multi-center pilot study for patients with relapsed G2/3 gliomas designed to match contemporaneous tissue obtained at the time of disease progression with subsequent targeted therapies. The objective was to establish the feasibility of a precision oncology, umbrella approach to obtain and type tissue within a useful timeframe. As a key feature of LUMOS, a multidisciplinary Molecular Tumor Advisory Panel (MTAP) with subspecialty neuro-oncology expertise was formed to interpret the complex genomic information and provide a simplified recommendation to the treating physician. RESULTS Ten patients (median age 42: range 32-62; four G2 astrocytoma, one G3 astrocytoma, three G2 oligoendroglioma, one G3 oligodendroglioma, one mixed tumor) were enrolled in the study. Eight patients had biopsies within 6 months of study entry whilst two underwent a biopsy during the study. All patients had potentially targetable alterations (10 IDH, 3 FGFR, 2 PIK3K, CCND3, NRAS, CDK4, PRPRZ1-MET fusion and MET amplification). Matched therapies were delivered for two patients via compassionate access outside the study. The median turnaround time (TAT) of MTAP reports was 6.2 weeks (range 4.2-9.7 weeks) but 4.6 weeks when lag time for shipping was removed. CONCLUSION LUMOS confirmed that this design was feasible with good turnaround times. The MTAP facilitated education and support for treating physicians. Thes findings support moving to a larger study using contemporaneous and longitudinal tissue samples matched with targeted therapies as part of a comprehensive umbrella study design. Delivery and interpretation of molecular data is a challenge shared across oncology which may be mitigated with a neuro-oncology specific molecular tumor board.

BACKGROUND Survival outcomes for patients with newly diagnosed glioblastoma have not changed significantly since the introduction of concurrent temozolomide with post-surgical radiation followed by adjuvant temozolomide. METHODS Multi-Arm Glioblastoma Australasia (MAGMA) is a recently initiated phase III multi-arm, multi-centre randomized trial for patients with newly diagnosed glioblastoma, led by the Australian Cooperative Trials Group for Neuro-Oncology (COGNO), that will concurrently test multiple treatment questions. Initially, a partial factorial design will be implemented to compare the current standard of care with either or both of (1) neoadjuvant temozolomide and (2) aduvant temozolomide continued beyond six months until progression. MAGMA will transition to a multi-arm multi-stage (MAMS) design as additional tratment question are introduced. Treatment allocation to each question will be balanced (1:1) using minimisation over several stratification factors, including study site, age, IDH-mutation status, surgical extent and randomization to the prior treatment question(s). The primary outcome is overall survival. Secondary outcomes include progression-free survival (measured by mRANO), time to first non-temozolomide systemic treatment, clinically significant toxicity as measured by Grade 2/4 adverse events, and health-related quality of life measures. Parsimonious data collection and a streamlined assessment schedule have been incorporated to mitigate the burden of data collection (such as low grade toxicity from temozolomide), and to encourage participation in regional and rural settings. A consortium model has been adopted to foster neuro-oncology expertise and infrastructure and share academic credit and future design opportunities. PROGRESS Recruitment commenced in September 2020. To date, 60 patients have been recruited from an initial sample size target of 250 patients for each of these initial two treatment questions. Of these 60 patients, 45 have been randomized in Question 1 (neoadjuvant chemotherapy) whilst 50 randomized in Question 2 (prolonged adjuvant chemotherapy). To date, 14 of the 27 intended sites are open to recruitment.

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.

The FIG study is a prospective non-randomised study now recruiting up to 210 newly diagnosed GBM participants across ten Australian sites. Study outcomes will address the role of [18F] fluoroethyl-L-tyrosine positron emission tomography (FET-PET) in radiotherapy (RT) planning, evaluation of post-treatment changes versus disease progression and prognostication. We describe here the methodology and preliminary outcomes for site credentialing. Eligible participants with GBM undergo FET-PET imaging at three time-points: FET-PET1-post-operative pre-chemo-RT, FET-PET2 acquired one month post-chemo-RT and FET-PET3 (+/-FDG-PET) triggered when clinical and/or radiological (MRI) progression is suspected. Dynamic and static FET-PET images are analysed qualitatively and quantitatively. Radiotherapy is as per standard care with the treating Radiation Oncologist (RO) blinded to FET-PET1. Site nuclear medicine (NM) physicians are required to delineate a biological target volume (BTV) based on FET-PET1 with hybrid RT volumes derived post-hoc. Pre-trial NM quality assurance comprises certification from the Australasian Radiopharmaceutical Trials Network encompassing FET-PET radiochemistry Quality Control and PET camera calibration. Site and central integrated workflows incorporating multi-modality image registration, target volume/region of interest contouring and analysis have been developed. NM benchmarking involves delineation of FET-PET BTVs in 3 cases with another 3 cases addressing response criteria interpretation harmonized across FET-PET, FDG-PET and MRI. Site ROs complete 3 cases involving standard and hybrid target volume delineation based on pre-derived FET-PET volumes. All NM and RO credentialing cases undergo central expert review. To date, of six sites which have submitted full credentialing data, 19/21 RO and 6/6 planning cases were passed. Of 72 NM cases, 18/72 (25%) required resubmission, primarily related to ensuring standardisation of background regions and time activity curve interpretation. The FIG study will be pivotal in establishing the role of FET-PET in GBM management. The robust NM and RO credentialing program will build capacity and expertise in FET-PET production, acquisition and image interpretation.

BackgroundIn patients with recurrent glioblastoma, the benefit of bevacizumab beyond progression remains uncertain. We prospectively evaluated continuing or ceasing bevacizumab in patients who progressed while on bevacizumab.MethodsCABARET, a phase II study, initially randomized patients to bevacizumab with or without carboplatin (Part 1). At progression, eligible patients underwent a second randomization to continue or cease bevacizumab (Part 2). They could also receive additional chemotherapy regimens (carboplatin, temozolomide, or etoposide) or supportive care.ResultsOf 120 patients treated in Part 1, 48 (80% of the anticipated 60-patient sample size) continued to Part 2. Despite randomization, there were some imbalances in patient characteristics. The best response was stable disease in 7 (30%) patients who continued bevacizumab and 2 (8%) patients who stopped receiving bevacizumab. There were no radiological responses. Median progression-free survival was 1.8 vs 2.0 months (bevacizumab vs no bevacizumab; hazard ratio [HR], 1.08; 95% CI, .59–1.96; P = .81). Median overall survival was 3.4 vs 3.0 months (HR, .84; 95% CI, .47–1.50; P = .56 and HR .70; 95% CI .38–1.29; P = .25 after adjustment for baseline factors). Quality-of-life scores did not significantly differ between arms. While the maximum daily steroid dose was lower in the continuation arm, the difference was not statistically significant.ConclusionsPatients who continued bevacizumab beyond disease progression did not have clear survival improvements, although the study was not powered to detect other than very large differences. While these data provide the only randomized evidence related to continuing bevacizumab beyond progression in recurrent glioblastoma, the small sample size precludes definitive conclusions and suggests this remains an open question.

BACKGROUND TMZ offers minimal benefit in pts with de novo uMGMT GBM. V is synergistic with RT and TMZ in uMGMT preclinical GBM models, safe when combined with either RT or TMZ clinically, but the triplet (V+RT+TMZ) is poorly tolerated. VERTU tested V in pts with uMGMT GBM. METHODS VERTU is a randomized Phase 2 trial comparing Standard Arm (Arm A), RT (60Gy/30 fractions) + TMZ (75mg/m2 daily) followed by TMZ (150–200mg/m2D 1–5) every 28 days for 6 cycles vs Experimental Arm (Arm B), RT (60Gy/30 fractions) + V (200mg PO BID) followed by TMZ (150–200mg/m2D 1–5) + V (40mg bid, D 1–7) every 28 days for 6 cycles in pts with de novo uMGMT GBM according to centralised testing. RESULTS 125 pts were randomized 1:2 (41:84). The 2 groups were matched for age, sex, performance status and extent of resection. Median follow-up was 25.8 months and 91 pts had died. The 6-month Progression-Free Survival (6mPFS) for Arms A and B were 34% (95% CI 20–48) and 46% (95% CI 36–57) respectively. The median PFS for Arms A and B were 4.2m (95% CI 2.5–6.0) and 5.7m (95% CI 4.1–6.6) respectively (HR = 0.80, 95%CI 0.55–1.18). 55% of pts in both arms experienced Grade 3/4 adverse events (AEs) with no significant differences in frequency or severity between the arms. Most common Grade 3/4 AEs were thrombocytopenia, seizures, hyperglycaemia and diarrhoea. CONCLUSION VERTU demonstrated that a novel treatment strategy for patients with de novo uMGMT GBM was feasible and tolerable. The observed 6mPFS and PFS were similar in both arms. Overall survival and other endpoints will be presented. Central MRI review, biomarker analyses, including DNA repair and methylation signature analyses are ongoing. (ANZCTR#ACTRN12615000407594).

Background. The optimal use of bevacizumab in recurrent glioblastoma (GBM), including the choice of monotherapy or combination therapy, remains uncertain. The purpose of this study was to compare combination therapy with bevacizumab monotherapy. Methods. This was a 2-part randomized phase 2 study. Eligibility criteria included recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, and Eastern Cooperative Oncology Group performance status 0-2. The primary objective (Part 1) was to determine the effect of bevacizumab plus carboplatin versus bevacizumab monotherapy on progression-free survival (PFS) using modified Response Assessment in Neuro-Oncology criteria. Bevacizumab was given every 2 weeks, 10 mg/kg; and carboplatin every 4 weeks, (AUC 5). On progression, patients able to continue were randomized to continue or cease bevacizumab (Part 2). Secondary endpoints included objective radiological response rate (ORR), quality of life, toxicity, and overall survival (OS). Results. One hundred twenty-two patients (median age, 55y) were enrolled to Part 1 from 18 Australian sites. Median follow-up was 32 months, and median on-treatment time was 3.3 months. Median PFS was 3.5 months for each arm (hazard ratio [HR]: 0.92, 95% CI: 0.64-1.33, P =. 66). ORR was 14% (combination) versus 6% (monotherapy) (P =. 18). Median OS was 6.9 (combination) versus 7.5 months (monotherapy) (HR: 1.18, 95% CI: 0.82-1.69, P =. 38). The incidence of bevacizumab-related adverse events was similar to prior literature, with no new toxicity signals. Toxicities were higher in the combination arm. Part 2 data (n = 48) will be reported separately. Conclusions. Adding carboplatin resulted in more toxicity without additional clinical benefit. Clinical outcomes in patients with recurrent GBM treated with bevacizumab were inferior to those in previously reported studies.

BACKGROUND: An increase of mutations as we age is well documented in GBM and in cancer in general. Elderly patients with GBM may have higher mutational burden and may be more likely to respond to immunotherapies. NUTMEG is a randomised Phase II study comparing post radiation NivolUmab and TMZ versus TMZ alone in Elderly patients with newly diagnosed GBM. METHODS: 102 patients will be randomized in a 2:1 allocation to receive short course RT (40Gy/15 daily fractions) and TMZ 75mg/m2) followed by 6 cycles of adjuvant TMZ (150-200mg/m2 days (D) 1–5 q28 days) with Nivolumab (240 mg D1, 15 q28 days for cycles (C) (1–4; 480 mg D1 Q 28 days for C5-6) versus 6 cycles of adjuvant TMZ (150-200mg/m2 D1-5 q28) alone. The study is stratified for ECOG performance status, age (< 70 vs 70), MGMT methylation and extent of resection. An independent safety monitoring committee is overseeing the trial and will review safety data for the first 10 patients treated on the experimental arm (TMZ + Nivolumab). The primary endpoint is Overall Survival (OS). Secondary endpoints include: 6 month Progression Free Survival, adverse events (AEs) and immune AEs, Quality of life, neurological function (NANO Scale), and correlation of modified RANO and iRANO in the experimental arm. Translational research endpoints include correlation of clinical endpoints with mutational burden, comprehensive immune characteristics and novel MRI sequences including pH-weighted MRIs. The expected proportion of patients alive at 24 months is predicted to be 15.7%. A hazard ratio of more than 0.69 in favour of the Nivolumab + TMZ arm will be considered sufficient to warrant further investigation including converting this study into a phase III trial. PROGRESS: At 3 June 2018, 6/18 study sites are open in Australia with 5 patients randomized. ACTRN12617000267358.

BACKGROUND: TMZ with short course radiotherapy (RT) is an option for elderly GBM patients. Nivolumab is a PD-1 inhibitor with known safety profile in GBM. An increase of mutations as we age is well documented in GBM and in cancer in general. A higher mutational load is associated with increased response to nivolumab. NUTMEG examines activity of nivolumab added to TMZ in GBM patients 65 years or older. METHODS: NUTMEG patients will receive RT (40Gy/15 fractions) concurrently with TMZ 75mg/m2. Post-radiation, the experimental group will receive nivolumab (240 mg days 1 and 15 Q 28 days for cycles 1–4; then 480 mg day 1 Q 28 days for cycles 5–6) with adjuvant TMZ (150-200mg/m2 days 1–5 Q 28 days) for 6 cycles. The standard treatment group will receive same dose and schedule of TMZ. The primary endpoint is Overall Survival (OS). Secondary endpoints include: 6-month (mo) Progression Free Survival (PFS-6), adverse events using NCI CTCAE v4.03 incorporating immune related AEs, QoL (EORTC QLQ-30, BN-20, and EuroQol EQ-5D-5L), Neurologic Assessment in Neuro-Oncology (NANO) Scale and correlation between modified RANO and immune-related RANO in the experimental arm. Translational research (TR) endpoints include mutational burden deciphered by whole exome sequencing; immune-related markers PD-L1, CD3+, CD4+, CD8+ and FOXP3 tumour infiltrating lymphocytes (TILs) and correlation with clinical outcomes. Advanced MRI will assess distribution of perfusion and diffusion, 3D morphometric and texture features and pH-weighted imaging correlated with clinical and TR endpoints. Safety will be reviewed by an independent data safety monitoring committee. Assuming a median OS of 9 mo, and accrual of 18mo and ≥24 mo follow-up 102 patients will be randomized in a 2:1 allocation (68 in the experimental arm and 34 in the control arm). This randomized phase II design targets a hazard ratio (HR) TMZ + nivolumab: TMZ for survival between experimental and control arms with a 90% CI of HR/1.46 to HR*1.46. If the upper limit is less than 1, we would conclude TMZ + nivolumab to be superior to warrant further investigation. This phase II design may be converted to a larger phase III trial if, at the end of the study, the number of events is sufficiently large. PROGRESS: At 28 May 2018, 5/18 study sites are open in Australia with 5 patients randomized. ACTRN12617000267358. Supported by NHMRC Project grant APP1125204 and Bristol-Myers Squibb.