Introduction:Magnetic resonance-guided radiotherapy enables repeated on-treatment imaging during chemoradiotherapy for glioblastoma (GBM), providing an opportunity to study dynamic tumor changes. We evaluated longitudinal volumetric change and spatial migration of T2/FLAIR signal abnormalities during treatment using a 1.5 T MR-Linac and examined their association with early disease progression. Methods:GBM patients suitable for chemoradiation on a 1.5 T MR-Linac were prospectively enrolled. Regions of T2/FLAIR signal abnormalities were contoured at baseline (F0), during selected treatment fractions, and at one-month post-radiotherapy (PM1). Tumor dynamics were quantified using percentage change in volume relative to F0 (Vrel) and migration distance (dmigrate), defined as the maximum linear displacement relative to F0. Patients were classified as early progressors (disease progression within 6 months after chemoradiation) or non-early progressors. Linear mixed-effects models evaluated longitudinal differences by early progression status, methylation, and extent of resection. Results:Thirty-three patients were included; 28 had ≥ 6 months follow-up and 12 were classified as early progressors. In adjusted linear mixed-effects models, Vrel was higher in early progressors than in non-early progressors from F7 onward (all p < 0.025), with larger differences later in treatment (F15: 38%, p = 0.004; F30: 104%, p = 0.019). Median Vrel was 2% at F1, 2% at F15, and 18% at F30. Median dmigrate increased from 5.0 mm at F1 to 12.6 mm at F30 and was higher in early progressors from F19 onward (difference 5.9 mm, p = 0.02) and at F30 (8.5 mm, p = 0.01). At end of treatment, Vrel ≥ 10% occurred in 12/28 patients (43%) and dmigrate ≥ 10 mm in 13/28 (46%). Among patients with Vrel ≥ 10%, 10/12 (83%) were early progressors; among those with dmigrate ≥ 10 mm, 9/13 (69%) were early progressors. Conclusion:Serial 1.5 T MR-Linac imaging enables longitudinal assessment of T2/FLAIR abnormality volume (Vrel) and spatial migration (dmigrate) during chemoradiotherapy for glioblastoma. Greater increases in Vrel and dmigrate were associated with early progression, supporting the potential role of on-treatment imaging in informing risk-adapted MR-guided radiotherapy strategies.

Purpose:The magnetic resonance linear accelerator (MRL) enables daily adaptation of radiation therapy plans. This study presents our institutional experience with the clinical outcomes and quality of life (QoL) of glioblastoma patients treated using a 1.5 Tesla (T) MRL. Materials and Methods:Eligible patients with glioblastoma were enrolled in a study and treated with MRL between August 2021 and May 2024. Acute toxicity was assessed. QoL was evaluated using the EORTC QLQ-C30 and QLQ-BN20 questionnaires. Cumulative overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier analysis. Results:27 patients were included, with a median follow-up of 12.2 months (range 0.5-30.6 months). The mean age was 63 years; 14 were male and had an ECOG performance status of 0-1. Eleven patients underwent gross total resection, 9 had subtotal resection, and 7 had biopsy only. 11 were MGMT-methylated, 15 nonmethylated, and 1 had unknown status. Twenty-five received their first radiotherapy course on the MRL. The mean interval from CT/MRI simulation to radiotherapy start was 12.6 days. 26 patients completed all prescribed fractions on the MRL. The median on-table treatment time per fraction was 28.2 (range: 11.7-66.5) minutes. Eleven patients (39.3%) required Adapt-To-Shape or re-planning within the first week due to tumor progression, indicated by increased T2/FLAIR signal beyond the initial CTV. No Grade 3-4 toxicities were reported. At 3 months, treatment was associated with declines in QoL domains at 3 months with recovery by 6 months. The median OS and PFS were 14.1 and 11.2 months. Conclusion:Treatment of glioblastoma with MR-guided adaptive radiotherapy is feasible, with manageable acute toxicities and adaptive capabilities to address tumor changes.

PURPOSE:To conduct a phase I and biodistribution study of the EphA3 antibody ifabotuzumab and zirconium-89-labeled ifabotuzumab (89Zr-ifabotuzumab) in patients with glioblastoma (GBM). PATIENTS AND METHODS:This multisite study was conducted in adults with recurrent GBM whose tumors were measurable according to Response Assessment in Neuro-Oncology (RANO) criteria and whose Eastern Cooperative Oncology Group performance status was 0 to 1. Patients underwent a biodistribution study with PET scans with 89Zr-ifabotuzumab, followed by three infusions of ifabotuzumab at either 3.5 or 5.25 mg/kg before undergoing a second study with 89Zr-ifabotuzumab PET scans. Resected patient diagnostic tumor samples were collected for multiplex immunofluorescence and spatial transcriptomics analyses. RESULTS:Twelve patients were recruited, of which six were treated with 3.5 mg/kg and six with 5.25 mg/kg of ifabotuzumab. 89Zr-ifabotuzumab and associated PET scanning were well tolerated, as was ifabotuzumab. There were no objective responses, but one patient had prolonged stable disease. In addition, two patients showed changes in peritumor edema that were suggestive of modulation of tumor vasculature. 89Zr-ifabotuzumab scans showed highly specific tumor uptake in all patients concordant with disease sites on MRI and PET imaging, without evidence of nonspecific binding. Spatial transcriptomics and immunofluorescence analyses of the patient's archival tissue specimens showed that EphA3 was expressed in the tumor microenvironment in all patients and tumor cells with different transcriptional states. CONCLUSIONS:Targeting EphA3 with ifabotuzumab in patients with GBM is safe and attractive, showing chronologic stable expression across both tumor compartments (particularly in cells with a mesenchymal phenotype) and nontumor compartments (particularly the vascular compartment) with evidence of target modulation.

Background:There are limited options for patients with relapsed glioma. Carboplatin is infrequently used for the treatment of recurrent gliomas, but there are anecdotal cases of benefit, although it has not been systematically studied in this setting. The aim of this study is to evaluate carboplatin monotherapy at a single tertiary center and characterize the efficacy and tolerability of carboplatin monotherapy in patients with recurrent glioma. Methods:Retrospective study of adult patients with histologically proven glioma (2016 WHO grade II-IV), treated with carboplatin monotherapy between March 2012 and May 2021 after progression on first-line treatment. Data extracted from electronic medical records includes baseline characteristics, previous treatments, carboplatin treatment, survival outcomes, and toxicities. Results:Sixty-three patients were included. Median age was 51 years (range 19-83). Fifty-three patients were grade IV at time of commencement of carboplatin (42 IDH1-wildtype) and 10 were grade II or III (6 astrocytomas, 4 oligodendrogliomas). As best response to carboplatin, 5 patients (8%) demonstrated tumor response on MRI, 17 patients (27%) remained stable, and 41 patients (65%) progressed. Median overall survival and progression-free survival were 6 months and 2 months, respectively. IDH1-mutant patients showed improved median overall survival (18 months, P = .0022) compared to IDH1-wildtype patients (6 months). Patients with oligodendrogliomas demonstrated longer median overall survival (22 months), which was significant compared to median overall survival of 5 months in glioblastoma (P = .0013). Carboplatin was well tolerated and toxicity was minimal. Conclusions:Carboplatin monotherapy in adult patients with relapsed glioma demonstrates minimal efficacy and toxicity but may be beneficial in oligodendrogliomas.

BACKGROUND:The Victorian Tumour Summits are an initiative to engage clinicians and consumers in identifying unwarranted variations in cancer care across the state. The Brain Tumour Summit reviewed the epidemiology, treatment, and outcomes of brain tumor patients for this purpose in 2020. METHODS:A retrospective analysis of Victorian brain cancer patients diagnosed between 2013 and 2017 was performed using linked Department of Health administrative datasets including the Victorian Cancer Registry; the Victorian Admitted Episodes Dataset; Victorian Radiotherapy Minimum Data Set; Victorian Emergency Minimum Dataset; and Victorian/National Death Index. RESULTS:A total of 2182 brain cancer patients were included, with a median age of 62 years and male predominance (59%). Most were histologically confirmed (90%). The largest group was glioblastoma (64%) followed by lower grade astrocytomas (14%) and oligodendrogliomas (5%). Nearly all surgery was undertaken in tertiary metropolitan sites regardless of patients' region of residence. Most high-grade glioma patients subsequently received radiotherapy. Radiotherapy for all glioma patients was mostly (75%) delivered by local health service providers. Data regarding oral chemotherapy were not available. CONCLUSIONS:Victorian patients had comparable outcomes across different regions, which are consistent with the published literature. The Summit identified three key areas of improvement that could improve patient outcomes and experience: identifying causes of variation in length of hospital stay after surgery and reducing length of stay where appropriate; harmonization of time to start radiotherapy across regional and metropolitan centers; and improved access to palliative care planning and utilization.

INTRODUCTION:Antibody drug conjugates (ADCs) are now a proven therapeutic class for many cancers, combining highly specific targeting with the potency of high effective payloads. This review summarizes the experience with ADCs in brain tumors and examines future paths for their use in these tumors.AREAS COVERED:This review will cover all the key classes of ADCs which have been tested in primary brain tumors, including commentary on the major trials to date. The efficacy of these trials, as well as their limitations, will put in context of the overall landscape of drug development in brain tumors. Importantly, this review will summarize key learnings and insights from these trials that help provide the basis for rational ways in which these drugs can be effectively and appropriate developed for patients with primary brain tumors.EXPERT OPINION:ADC development in brain tumors has occurred in two major phases to date. Key learnings from previous trials provide a strong rationale for the continued development of these drugs for primary brain tumors. However, the unique biology of these tumors requires development strategies specifically tailored to maximize their optimal development.

Medulloblastoma in adult patients is a rare condition with limited contemporary demographic and treatment outcome data available in an Australian population. We conducted a retrospective review of patterns of care and outcomes of adult patients diagnosed with medulloblastoma treated at major neuro-oncology centres across Australia between January 2010 and December 2019. A total of 80 patients were identified and the median follow-up after diagnosis was 59.2 (range 0.5-204) months. A variety of chemotherapy regimens were used in the adjuvant and recurrent settings. The median overall survival (mOS) was 78 months (IQR 17.5-94.8). Patients who had no residual disease post-resection or with SHH-subtype tumours had a numerically longer 5-year survival rate than those with residual disease post resection or non-SHH subtypes respectively. The median time to recurrence from diagnosis was 18.4 months. The median OS from 1st relapse was 22.1 months (95% CI 11.7-31.4) and mOS from second relapse was 10.2 months (95% CI 6.6 - NR). This is the largest dataset examining patterns of care of adult patients with medulloblastoma in an Australian population. Substantial variation existed in the chemotherapy agents used in the adjuvant and recurrent setting. As has been demonstrated in a paediatric population, trials such as the upcoming EORTC 1634-BTG/NOA-23 trial (PersoMed-1 study) which are tailoring treatments to molecular profiles are likely to improve outcome in adult medulloblastoma.

Abstract Introduction The VEGF pathway remains an important target in GBM given its vascularity and autocrine VEGF signalling. Olinvacimab is a fully humanised VEGFR2 monoclonal antibody that binds and inhibits the receptor. This report assesses the safety, dosing schedules and efficacy of olinvacimab in recurrent GBM (rGBM). Methods Adult patients with a measurable lesion, histopathological diagnosis of primary GBM with tumour progression after chemoradiotherapy were included. No prior biologic treatment was allowed. Three dose levels of intravenous olinvacimab were assessed: 8 mg/kg (dose level 1) and 12mg/kg (dose level 2) weekly for 3 out of 4 weeks, and 12 mg/kg weekly (dose level 3). Efficacy was assessed by MRI using RANO criteria. Dynamic Contrast-Enhanced MRIs (DCE-MRIs) were analysed for changes in perfusion parameters during treatment. Results Twelve patients were enrolled in this study: three each in dose levels 1 and 2, and six in dose level 3. The main toxicity was development of grade 1 (67%) and 2 (8%) cutaneous haemangiomas. Common toxicities noted with other VEGF directed therapies- including hypertension, impaired wound healing, and proteinuria- were not seen. The 6-month progression free survival rate was 17%, disease control rate 25%, and the longest response 15 months. No significant difference in perfusion parameters was found between baseline and 1st follow-up DCE-MRI comparing those with stable and progressive disease. ConclusionOlinvacimab was well tolerated across three dose levels and had a distinct toxicity profile. Disease control was seen in 25% of patients and warrants further follow up in further clinical trials.

The advent of systemic therapies with high intracranial efficacy in recent years is changing the therapeutic paradigm and renewing interest in the management of central nervous system (CNS) and leptomeningeal metastases from solid organ tumors. CNS metastases have traditionally heralded a dismal prognosis with median survival of 3-10 months, and were primarily treated with local therapeutic modalities, such as surgery or radiation therapy. Although these modalities still have a role in the management of CNS disease, newer agents, such as small molecule tyrosine kinase inhibitors and immune-checkpoint inhibitors, are now paving the way as an alternative therapeutic option for those with oligometastatic or low-volume intracranial disease, potentially eliminating or delaying the need for local treatment modalities in this setting. Herein, we summarize the systemic treatments with proven intracranial efficacy, currently approved for use in Australia for advanced mutation-driven non-small cell lung cancer, melanoma, and breast cancer, as well as novel agents in preclinical and clinical trial development.

Limited progress has been made in treating glioblastoma, and we hypothesise that poor concordance between preclinical and clinical efficacy in this disease is a major barrier to drug development. We undertook a systematic review to quantify this issue. We identified phase I trials (P1Ts) of tumor targeted drugs, subsequent trial results and preceding relevant preclinical data published in adult glioblastoma patients between 2006–2019 via structured searches of EMBASE/MEDLINE/PUBMED. Detailed clinical/preclinical information was extracted. Associations between preclinical and clinical efficacy metrics were determined using appropriate non-parametric statistical tests. A total of 28 eligible P1Ts were identified, with median ORR of 2.9% (range 0.0–33.3%). Twenty-three (82%) had published relevant preclinical data available. Five (18%) had relevant later phase clinical trial data available. There was overall poor correlation between preclinical and clinical efficacy metrics on univariate testing. However, drugs that had undergone in vivo testing had significantly longer median overall survival (7.9 vs 5.6mo, p = 0.02). Additionally, drugs tested in ≥ 2 biologically-distinct in vivo models (‘multiple models’) had a significantly better median response rate than those tested using only one (‘single model’) or those lacking in vivo data (6.8% vs 1.2% vs. 0.0% respectively, p = 0.027). Currently used preclinical models poorly predict subsequent activity in P1Ts, and generally over-estimate the anti-tumor activity of these drugs. This underscores the need for better preclinical models to aid the development of novel anti-glioblastoma drugs. Until these become widely available and used, the use of multiple biologically-distinct in vivo models should be strongly encouraged.

Abstract Overview Glioblastoma multiforme (GBM) is the most frequent and lethal primary brain neoplasm, with only 10% of patients surviving 5 years.1 EphA3 is a tumor restricted antigen expressed in various solid tumors and the tumor vasculature of 100% of GBM.2,3 Ifabotuzumab is a non-fucosylated IgG1κ humaneered antibody targeting the EphA3 receptor.4 A Phase I study of ifabotuzumab in haematological malignancies showed it was well tolerated and clinically active.5 Here we report on a Phase I dose escalation and biodistribution study of ifabotuzumab in recurrent GBM. Study Design The primary objective is to determine the safety and recommended Phase II dose of ifabotuzumab in GBM patients (pts). Secondary objectives are to determine the biodistribution and pharmacokinetics (PK) of 89Zr- ifabotuzumab, the frequency of EphA3 positive GBM and response rates. On day 1, eligible pts with measurable tumors received a trace (5mg) dose of zirconium labelled ifabotuzumab (89Zr-ifab) followed by sequential PET imaging over 1 week to determine its biodistribution, frequency of in situ EphA3 expression and quantitative tumor uptake. Safety assessments and PK sampling were also undertaken. On day 8, pts commenced weekly ifabotuzumab infusions over 2 hours in one of two cohorts (3.5mg/kg, 5.25 mg/kg). On day 36, pts received both 89Zr-ifab and ifabotuzumab, allowing assessment of receptor occupancy. Response rate (RANO) and survival data were collected. Pts then continued on ifabotuzumab until progression. Results In total, 12 pts have been enrolled, including 6 in the 3.5mg/kg and 6 in the 5.25 mg/kg dose cohorts. Mean age was 51.6 years (±14.24) and 7/12 pts were male. Treatment emergent adverse events included infusion reactions in 4 pts, seizures in 3 pts, cerebral oedema in 1, rash in 1, headaches in 8, eye disorder in 1. Most were considered related to study drug except seizure in 2 pts, headaches and eye disorder. Seizures and infusion reactions were readily managed with increased premedications after the first occurrence. The best response was stable disease for 23 weeks. 89Zr-ifab-PET scans showed rapid, tumor-specific targeting at all known tumor sites and in all pts, but with no normal tissue uptake. MRI scans showed predominant T2/FLAIR changes, occasionally marked, which were consistent with treatment effect of ifabotuzumab on tumor vasculature. The mean ± SD (n=12) PK parameters for first infusion 89Zr-ifab were T½α= 9.03 ± 4.45 hr, T½β = 92.50 ± 65.65 hr, V1 = 3.75 ± 0.67 L, CL= 132.11 ± 70.16 mL/hr. Conclusions: Ifabotuzumab demonstrates highly sensitive, specific and reproducible targeting of the tumor and tumor microenvironment in all patients in this study. The imaging changes suggest direct modulation of the tumor vasculature. Additional studies are planned to evaluate ifabotuzumab as part of an antibody-drug conjugate in various solid tumor types. References: 1. Stupp R, et al, Lancet Oncology 10:459-66, 2009 2. Day BW, et al. Cancer Cell 23:238-48, 2013 3. Vail ME, et al. Cancer Research 74:4470-81, 2014 4. Tomasevic N, et al. Growth Factors 32:223-35, 2014 5. Swords RT, et al. Leukemia Research 50:123-131, 2016 Citation Format: Hui K. Gan, Lawrence Cher, Po Inglis, Zarnie Lwin, Eddie Lau, Christian Wichmann, Alex McDonald, Ashray Gunjur, Uwe Ackermann, Kirsten Remen, Kate Fluck, Gel Bolarnos, Nancy Guo, Sze Ting Lee, Sylvia Gong, Jodie B. Palmer, Kunthi Pathmaraj, Graeme J. O'Keefe, Fiona E. Scott, Bryan W. Day, Andrew W. Boyd, Paul Thomas, Omar Ahmed, Dale Chappell, Cameron Durrant, Andrew M. Scott. Phase I safety and bioimaging trial of ifabotuzumab in patients with glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT101.

Introduction Grades 2 and 3 gliomas (G2/3 gliomas), when combined, are the second largest group of malignant brain tumours in adults. The outcomes for G2/3 gliomas at progression approach the dismal outcomes for glioblastoma (GBM), yet there is a paucity of trials for Australian patients with relapsed G2/3 gliomas compared with patients with GBM. LUMOS will be a pilot umbrella study for patients with relapsed G2/3 gliomas that aims to match patients to targeted therapies based on molecular screening with contemporaneous tumour tissue. Participants in whom no actionable or no druggable mutation is found, or in whom the matching drug is not available, will form a comparator arm and receive standard of care chemotherapy. The objective of the LUMOS trial is to assess the feasibility of this approach in a multicentre study across five sites in Australia, with a view to establishing a national molecular screening platform for patient treatment guided by the mutational analysis of contemporaneous tissue biopsies Methods and analysis This study will be a multicentre pilot study enrolling patients with recurrent grade 2/3 gliomas that have previously been treated with radiotherapy and chemotherapy at diagnosis or at first relapse. Contemporaneous tumour tissue at the time of first relapse, defined as tissue obtained within 6 months of relapse and without subsequent intervening therapy, will be obtained from patients. Molecular screening will be performed by targeted next-generation sequencing at the reference laboratory (PathWest, Perth, Australia). RNA and DNA will be extracted from representative formalin-fixed paraffin embedded tissue scrolls or microdissected from sections on glass slides tissue sections following a review of the histology by pathologists. Extracted nucleic acid will be quantified by Qubit Fluorometric Quantitation (Thermo Fisher Scientific). Library preparation and targeted capture will be performed using the TruSight Tumor 170 (TST170) kit and samples sequenced on NextSeq 550 (Illumina) using NextSeq V.2.5 hi output reagents, according to the manufacturer’s instructions. Data analysis will be performed using the Illumina BaseSpace TST170 app v1.02 and a custom tertiary pipeline, implemented within the Clinical Genomics Workspace software platform from PierianDx (also refer to section 3.2). Primary outcomes for the study will be the number of patients enrolled and the number of patients who complete molecular screening. Secondary outcomes will include the proportion of screened patients enrolled; proportion of patients who complete molecular screening; the turn-around time of molecular screening; and the value of a brain tumour specific multi-disciplinary tumour board, called the molecular tumour advisory panel as measured by the proportion of patients in whom the treatment recommendation was refined compared with the recommendations from the automated bioinformatics platform of the reference laboratory testing. Ethics and dissemination The study was approved by the lead Human Research Ethics Committee of the Sydney Local Health District: Protocol No. X19-0383. The study will be conducted in accordance with the principles of the Declaration of Helsinki 2013, guidelines for Good Clinical Practice and the National Health and Medical Research Council National Statement on Ethical Conduct in Human Research (2007, updated 2018 and as amended periodically). Results will be disseminated using a range of media channels including newsletters, social media, scientific conferences and peer-reviewed publications. Trial registration number ACTRN12620000087954; Pre-results.

Abstract Background Improving outcomes of patients with glioblastoma (GBM) represents a significant challenge in neuro-oncology. We undertook a systematic review of key parameters of phase II and III trials in GBM to identify and quantify the impact of trial design on this phenomenon. Methods Studies between 2005 and 2019 inclusive were identified though MEDLINE search and manual bibliography searches. Phase II studies (P2T) were restricted to those referenced by the corresponding phase III trials (P3T). Clinical and statistical characteristics were extracted. For each P3T, corresponding P2T data was “optimally matched,” where same drug was used in similar schedule and similar population; “suboptimally matched” if dis-similar schedule and/or treatment setting; or “lacking.” Phase II/III transition data were compared by Pearson Correlation, Fisher’s exact or chi-square testing. Results Of 20 P3Ts identified, 6 (30%) lacked phase II data. Of the remaining 14 P3T, 9 had 1 prior P2T, 4 had 2 P2T, and 1 had 3 P2T, for a total of 20 P3T-P2T pairs (called dyads). The 13 “optimally matched” dyads showed strong concordance for mPFS (r2 = 0.95, P < .01) and mOS (r2 = 0.84, P < .01), while 7 “suboptimally matched” dyads did not (P > .05). Overall, 7 P3Ts underwent an ideal transition from P2T to P3T. “Newly diagnosed” P2Ts with mPFS < 14 months and/or mOS< 22 months had subsequent negative P3Ts. “Recurrent” P2Ts with mPFS < 6 months and mOS< 12 months also had negative P3Ts. Conclusion Our findings highlight the critical role of optimally designed phase II trials in informing drug development for GBM.

Abstract The VEGF pathway remains an important target in GBM given its vascularity and autocrine VEGF signalling. Olinvacimab (TTAC-0001) is a fully humanised VEGFR2 Mab that binds and inhibits the receptor. This report assesses the safety, dosing schedules and efficacy of Olinvacimab in recurrent GBM. We conducted a two-site, 3 arm, open-label study of Olinvacimab in recurrent GBM. Eligible patients were ≥18 years with RANO-measurable lesion, KPS ≥ 80, and had completed chemoradiotherapy without prior bevacizumab therapy. We assessed three arms, 8 mg/kg and 12mg/kg weekly for 3 of every 4 weeks, and 12 mg/kg weekly. Three patients were treated in arms 1 and 2 and 6 in arm 3. Safety assessments were performed prior to dose escalation. The main toxicity was development of grade 1 (67%) and 2 (8%%) cutaneous haemangiomas. Common toxicities seen with other VEGF directed therapies, including hypertension, impaired wound healing, and proteinuria were not seen in this cohort. Efficacy was assessed by MRI using RANO criteria. 6 month PFS was 17%, with disease control in 25%, with steroid dose reduction. The longest response was 15 months. On DCE MRI, there was no significant difference in perfusion parameters between baseline and 1st follow-up MRI comparing those with SD and PD. However, 6 of 12 patients showed decreased Ktrans > 20 % of baseline, consistent with an anti-angiogenic effect of Olinvacimab. Pharmacokinetics showed a decreased clearance rate and increased half-life of Olinvacimab compared to the prior Phase I study. Pharmacodynamic studies showed significantly higher levels of angiogenic markers, particularly VEGF-A in those treated at 12mg/kg vs arm 1. VEGF-A, C and D levels were elevated in patients with SD compared to those with PD. Conclusion: Olinvacimab was well tolerated with a different toxicity profile to other VEGFR directed therapies. There were promising responses in 25% of patients.

Abstract INTRODUCTION No drug has improved survival in recurrent glioblastoma despite encouraging activity preclinically. We undertook a systematic review of matched preclinical and Phase 1 trials (P1Ts) of targeted agents to investigate potential preclinical predictors of clinical efficacy. METHODS We identified all adult glioblastoma monotherapy P1Ts of targeted agents & preceding preclinical data published between 2006–2019 via structured searches of EMBASE/MEDLINE/PUBMED. For preclinical studies, data regarding in vitro models, in vivo models (species, implantation site, cell-line type) and efficacy (growth inhibition, regression rate, survival) were extracted. For P1T, response rate (RR) data were collected as absolute (%) and categorical (RR< 5% vs. RR≥ 5%) variables. Associations were compared by chi-square/Fisher’s exact test, Kruskal-Wallis or Mann-Whitney U testing as appropriate with 2-sided p-values. RESULTS We found 28 P1Ts with median RR 2.9% (range 0.0–33.3%) and mOS 8.0mo (range 4.6–13.0mo). Seven (25%) had ‘minimal’ published pre-clinical data (5 missing entirely; 2 in vitro only); 12 (43%) utilised one cell line in vivo (‘single model’ group); and 9 (32%) used 2+ biologically distinct in vivo models (‘orthogonal’ group). There was strong reliance on U87-based cell lines (14/21 (71%)) in the latter groups. None of the variables tested were associated with RR except for use of ‘orthogonal models’. Compared to the ‘orthogonal’ group, the P1T RR rate was lower in ‘single’ and ‘minimal’ groups (6.8% vs 1.2%, p= 0.043 and 6.8% vs 0.0%, p= 0.026 respectively). The frequency of P1T with a RR > 5% was also higher in the ‘orthogonal’ compared to the same two groups (78% vs 20%, p= 0.042 and 78% vs 17%, p= 0.041). CONCLUSION The availability of good quality pre-clinical data, especially the use of orthogonal models in vivo, was significantly associated with P1T response rates and warrants further investigation as a minimal threshold of evidence in future drug development.

1562 Objectives: Glioblastoma multiforme (GBM) is the most frequent and lethal primary brain neoplasm, with only 10% of patients surviving 5 years from diagnosis. EphA3 is a tumor restricted antigen expressed in 100% of the tumor vasculature as well as on some stromal cells in GBM, and other solid tumors. Ifabotuzumab is a non-fucosylated IgG1κ antibody targeting EphA3. A Phase I study of ifabotuzumab in hematological malignancies showed it to be well tolerated and clinically active. Here we report on a Phase I dose escalation and biodistribution study of ifabotuzumab in patients with recurrent GBM. Methods: Eligible patients received a trace (5mg) dose of zirconium-89 labelled ifabotuzumab (89Zr-ifab) on day 1 followed by sequential PET imaging over 1 week to determine its biodistribution and quantitative tumor uptake. Safety assessments and PK sampling were also undertaken. The primary objective is to determine the safety and recommended Phase II dose of ifabotuzumab in GBM patients. Secondary objectives are to determine the biodistribution and pharmacokinetics (PK) of 89Zr-ifabotuzumab, the frequency of EphA3-positive GBM, and response rates. On day 8, patients commenced weekly ifabotuzumab infusions over 2 hours in one of three cohorts planned (3.5mg/kg, 5.25 mg/kg, 7.9 mg/kg). On day 36, pts received both 89Zr-ifab and ifabotuzumab, allowing assessment of receptor occupancy. Response rate (RANO) and survival data were collected. Patients then continued on ifabotuzumab until disease progression. Results: To date, 8 of 12 planned patients have enrolled (6 at 3.5 mg/kg, 2 at 5.25 mg/kg). Mean age is 51 years (range 24-71 yrs) and 5 patients are male. Treatment emergent adverse events included infusion reactions in 3 patients, seizures in 2 patients, cerebral oedema in 2 patients, rash in 1 patient, pruritis in 1 patient, headaches in 7 patients and eye disorder in 2 patients. Most were considered related to study drug except seizure in 1 patient, headaches and eye disorder. Seizures and infusion reactions were readily managed with increased premedications after the first occurrence. The best response in cohort 1 (to date) is stable disease for 23 weeks.89Zr-ifab PET/CT scans showed rapid, specific targeting at all known tumor sites and in all patients, and no specific normal tissue uptake. No saturation of uptake of 89Zr-ifab in tumor was seen with unlabelled ifabotuzumab co-infusion. MRI scans showed predominant T2/FLAIR changes, occasionally marked, which were consistent with treatment effect on tumor vasculature. The mean ± SD PK parameters for first infusion of 89Zr-ifab were T½α 10.54 ± 4.52 hr, T½β = 101.51 ± 54.08 hr, V1 = 3.89 ± 0.66 L, CL= 108.37 ± 46.43 mL/hr. Conclusions: 89Zr-ifab demonstrates sensitive, specific and reproducible targeting of the tumor microenvironment in GBM patients. The imaging changes suggest modulation of the tumor vasculature and treatment effect. Enrolment is on-going.

Pilocytic astrocytomas are World Health Organisation (WHO) grade I tumors, occurring predominantly supratentorially and in the pediatric population. Although the mainstay of treatment is local therapies such as surgery, targeted systemic therapies may be necessary for recurrent or unresectable disease. The majority of sporadic pilocytic astrocytomas are associated with the BRAF-KIAA fusion gene, which results in constitutive activation of the MAP Kinase pathway. Less frequently, the BRAF V600E point mutation has been described, occurring in less than 10% of supratentorial pilocytic astrocytomas. Tumours with this mutation may respond to targeted therapy against the BRAF/MAP Kinase pathway. We report the first described case of a spinal pilocytic astrocytoma in an adult patient with a BRAF V600E mutation responding to targeted therapy using BRAF and MEK tyrosine kinase inhibitors, and share our experiences with the management of toxicity in this patient population.

e14545 Background: Recurrent GBM is difficult to treat. Single agent checkpoint blockade has not improved outcomes. Angiogenesis is a rational drug target for rGBM and targeting angiogenesis may benefit pseudoprogression and cerebral oedema. O is a fully human monoclonal antibody (MAB) which binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) with antiangiogenic and antitumour effects. P is an anti-PD1 MAB. This study aimed to identify the safety and tolerability of O combined with P and to establish a recommended phase 2 combination dose. Methods: From January to October 2019, we conducted a two-site, single arm, open-label study of O with P in patients with rGBM. Eligible patients (pts) were ≥18 years with at least one RANO-measurable lesion, KPS≥80, and had completed standard chemoradiotherapy and had no contraindications to O or P. No prior bevacizumab was allowed. A modified Toxicity Probability Interval design was used. Pts received O 12 mg/kg day 1/8/15 q21d (dose level 1) or O 16mg/kg day 1/8/15 q21d (dose level 2) in combination with P 200mg flat dose day 1 q21d. Pts were reviewed weekly and underwent DCE-MRI at baseline and 6-weekly. Treatment continued to progression, toxicity or withdrawal. Results: 9 pts, median age 53 (range 34-67) were recruited and received at least one study treatment. Median time since diagnosis was 15.6 months. 7 (78%) had KPS 90 and 2 (22%) KPS 80. 3 pts received O 12mg/kg with P, completing a median 3 cycles (range 2-6). As no Dose Limiting Toxicities (DLTs) were seen, 3 pts were treated with O 16mg/kg with expansion total 6 when no DLTs were observed. At 16mg/kg, a median of 2 treatment cycles was received (range 2-6). Treatment was ceased due to progressive disease (PD) in 8 pts with one ongoing at data cutoff. No DLTs were observed in any pts. Three grade 3 treatment emergent adverse events (TEAEs) were noted (blurred vision, fatigue, and seizure). Hemangioma is a known toxicity of O and was seen in 6 pts, with 11 grade 1 and 1 grade 2 event. 4 pts (44%) had stable disease (SD) and 5 pts (56%) had PD as best response. Conclusions: The combination of O with P was safe and tolerable at the full single agent dose of each drug. No DLTs were observed. The combination did not show efficacy in this setting. Clinical trial information: NCT03722342.

Tumor hypoxia is a centerpiece of disease progression mechanisms such as neoangiogenesis or aggressive hypoxia-resistant malignant cells selection that impacts on radiotherapy strategies. Early identification of regions at risk for recurrence and prognostic-based classification of patients is a necessity to devise tailored therapeutic strategies. We developed an image-based algorithm to spatially map areas of aerobic and anaerobic glycolysis (Glyoxia). 18F-FDG and 18F-FMISO PET studies were used in the algorithm to produce DICOM-co-registered representations and maximum intensity projections combined with quantitative analysis of hypoxic volume (HV), hypoxic glycolytic volume (HGV), and anaerobic glycolytic volume (AGV) with CT/MRI co-registration. This was applied to a prospective clinical trial of 10 glioblastoma patients with post-operative, pre-radiotherapy, and early post-radiotherapy 18F-FDG and 18F-FMISO PET and MRI studies. In the 10 glioblastoma patients (5M:5F; age range 51–69 years), 14/18 18F-FMISO PET studies showed detectable hypoxia. Seven patients survived to complete post-radiotherapy studies. The patient with the longest overall survival showed non-detectable hypoxia in both pre-radiotherapy and post-radiotherapy 18F-FMISO PET. The three patients with increased HV, HGV, and AGV volumes after radiotherapy showed 2.8 months mean progression-free interval vs. 5.9 months for the other 4 patients. These parameters correlated at that time point with progression-free interval. Parameters combining hypoxia and glycolytic information (i.e., HGV and AGV) showed more prominent variation than hypoxia-based information alone (HV). Glyoxia-generated images were consistent with disease relapse topology; in particular, one patient had distant relapse anticipated by HV, HGV, and AGV maps. Spatial mapping of aerobic and anaerobic glycolysis allows unique information on tumor metabolism and hypoxia to be evaluated with PET, providing a greater understanding of tumor biology and potential response to therapy.

2516 Background: Improving the outcomes of patients with glioblastoma (GBM) represents one of the most significant challenges in neuro-oncology. We have observed inefficiencies in the availability and use of phase 2 data when planning phase 3 studies, and have undertaken a detailed review of key design parameters of phase 2 and 3 trials in GBM to identify and quantify the impact of this phenomenon. Methods: Studies between 2005-2019 inclusive were identified though MEDLINE search using keywords and MeSH terms, and manual bibliography searches. P2Ts were restricted to those referenced by the corresponding P3Ts. Clinical, statistical and sponsor characteristics were extracted by two reviewers (AB&AG). For each P3T, corresponding Phase 2 trial (P2T) data was “optimally matched” (OM) where same drug was used in similar schedule and similar GBM population; “partially matched” (PM) where dis-similar schedule and/or treatment setting; and “lacking” in all other circumstances. The statistical data used in the P2/3 transition were compared by Pearson Correlation, Fisher’s Exact or Chi-square testing as appropriate. Results: Of 20 P3Ts identified, 6 (30%) lacked any phase 2 data. Of the remaining 14 P3T, 9 had 1 prior P2T, 4 had 2 P2T and 1 had 3 P2T, for a total of 20 P3T-P2T pairs (called dyads). Further, there were 13 OM dyads and 7 PM dyads. OM dyads showed strong concordance for mPFS (r2= 0.95, p < 0.01) and mOS (r2= 0.84, p < 0.01), whilst PM dyads did not (p > 0.05). We identified several inefficiencies in translation from P2T to P3T. Firstly, 3 P3T had statistical assumptions of primary endpoint that may have been too optimistic. 2 of these P3Ts aimed for an expected endpoint that was higher than the actual outcomes from a matched P2T. 1 P3T was unable to reach the desired sample size. We note that 4 P3Ts had actual primary endpoint HRs that were < 0.9 but with P > 0.05. Finally, we investigated whether there were absolute thresholds for efficacy in P2Ts to inform whether to proceed with P3Ts. For P2Ts in the newly diagnosed setting, all those with mPFS < 14 months and/or mOS < 22 months had subsequent negative P3Ts. For P2Ts in recurrent disease, all those with mPFS < 6 months and mOS < 12 months had negative P3Ts. Applying these thresholds to the studies in our review, 10 of the 12 negative P3Ts (83%) with matched P2Ts need not have been initiated, sparing 4739 patients’ from unnecessary trial participation. Conclusions: Our data strongly supports the vital role of properly designed P2Ts in informing P3Ts for drug development for primary CNS tumours.