Abstracts vii70 NEURO-ONCOLOGY • November 2022 differed signifcantly between the metastasis of different primary cancers signaling the importance of the primary cancer location in determining vi- able therapeutic targets. CTNI-02. PRECLINICAL DATA AND INITIAL CLINICAL EXPERIENCE IN THE PHASE 1/2A DOSE ESCALATION TRIAL OF RHENIUM-186 NANOLIPOSOME (186RNL) IN LEPTOMENINGEAL METASTASES [LM]: THE RESPECT-LM TRIAL Andrew Brenner 1 , Michael Youssef 2 , Norman LaFrance 3 , Marc Hedrick 3 , Ande Bao 4 , William Phillips 1 , Toral Patel 5 , Jeffrey Weinberg 6 , and John Floyd 1 ; 1 UT Health San Antonio, San Antonio, TX, USA, 2 UT Southwestern, Dallas, TX, USA, 3 PLUS Therapeutics, Austin, TX, USA, 4 The University Hospital Cleveland Medical Center, Cleveland, OH, USA, 5 UT Southwestern Med Center, Dallas, TX, USA, 6 MD Anderson Cancer Center, Houston, TX, USA INTRODUCTION: Leptomeningeal metastases (LM) is a clinical com- plication that occurs when cancer cells invade the leptomeninges and cere- brospinal fuid of patients with malignant tumors. Once diagnosed, limited treatment options exist, and survival is poor. Rhenium-186 Nanoliposome ( 186 RNL) is a liposomal encapsulated beta emitter with a short path length of 1.8 mm, thereby allowing high specifc activity brachytherapy with limited exposure to surrounding tissues. METHODS: Preclinical effcacy was as- sessed using C6-Luc glioma cells in Wistar rats or MDA-MB-231 in Athymic Nude Rats via intraventricular injection. At 15 days post inoculation the ani- mals were treated with 0.69 mCi of 186 RNL. Absorbed doses were assessed with gamma camera imaging at 0h, 24h, and 48h post-treatment. Tumor growth was assessed by luciferase bioluminescence. A multicenter phase 1/2a dose (3 + 3 design) escalation trial was then initiated with 186 RNL in LM patients to determine the maximum feasible dose, overall response rate (ORR) and overall survival distribution. RESULTS: A signifcant difference in survival between the control and treatment groups (n = 8 each) was ob- served in the C6/Wistar model at 2 weeks post treatment, with 50% survival in the control group and 100% survival in the treatment group (p = 0.0087). Similar effcacy was observed in the MDA-MB-236/Athymic model. Thus far two patients have received 186 RNL with 6.6 mCi in 5ml via Ommaya reservoir. Post treatment imaging shows full CSF distribution by 4 hours and persistence of activity through 7 days following administration. The dose was well-tolerated with no related AEs through day 56 following treat- ment. CSF cell count by BioCept analysis was reduced by > 90% with dur- ability through day 28. CONCLUSION: Intraventricular delivered 186 RNL is promising for treatment of LM, with very early evidence of effcacy in patients. Enrollment is ongoing. CTNI-03. A PHASE I/IIA, OPEN-LABEL STUDY OF THE BRAIN- PENETRANT PARP1-SELECTIVE INHIBITOR AZD9574 AS MONOTHERAPY AND IN COMBINATION IN PATIENTS WITH ADVANCED SOLID MALIGNANCIES (CERTIS1) Nancy Mueller 1 , Stephen Luen 2 , Roger Stupp 3 , Anthony Chalmers 4 , Baisong Huang 5 , Massimo Squatrito 6 , Barry Davies 7 , Petra Hamerlik 7 , and Timothy Yap 8 ; 1 AstraZeneca, Gaithersburg, MD, USA, 2 Peter MacCallum Cancer Centre, Melbourne, Australia, 3 Northwestern University — Neurological Surgery; Feinberg School of Medicine, Chicago, IL, USA, 4 University of Glasgow, Glasgow, United Kingdom, 5 AstraZeneca, Waltham, MA, USA, 6 AstraZeneca, Cambridge, United Kingdom, 7 AstraZeneca, Saffron Walden, United Kingdom, 8 University of Texas MD Anderson Cancer Center, Houston, TX, USA BACKGROUND: Currently approved Poly ADP-Ribose Polymerase (PARP) inhibitors (PARPi) selectively inhibit and trap both PARP1 and PARP2 (PARP1/2) at sites of single strand (ss) deoxyribonucleic acid (DNA) (ssDNA) damage, preventing ssDNA repair and leading to replication- dependent DNA double strand breaks. Recent data suggest that only in- hibition of PARP1 is required for anti-proliferative effects, while PARP2 functions in the survival of haematopoietic stem and progenitor cells. These observations suggest that the inhibition and trapping of PARP 2 is not needed for anti-cancer effects, and may be a major driver of haematological toxicity observed. AZD9574 is a novel brain-penetrant PARPi that potently and selectively inhibits and traps PARP1, with the goal of delivering effca- cious, less toxic, and more combinable PARPi. Furthermore, owing to its central nervous system penetration capability, AZD9574 may provide a new treatment option for patients with CNS malignancies or patients with brain metastases characterized by homologous recombination defciency (HRD).  METHODS: This is a frst-in-human modular study primarily designed to evaluate the safety and tolerability of AZD9574 as monotherapy and in combination with anti-cancer agents at increasing dose levels in patients with advanced solid malignancies, followed by expansion cohorts in spe- cifc indications. The study will also characterize the pharmacokinetics of AZD9574 and explore potential biological activity by assessing pharma- codynamic and exploratory biomarkers and anti-tumour activity. Module 1 will enrol patients with advanced breast, ovarian, pancreatic or prostate tumours harbouring homologous recombination defciencies. Module 2 will enrol patients with isocitrate dehydrogenase (IDH)1/2 mutated glioma. CTNI-04. TRAM-01: A PHASE 2 STUDY OF TRAMETINIB FOR PEDIATRIC PATIENTS WITH NEUROFIBROMATOSIS TYPE 1 AND PLEXIFORM NEUROFIBROMAS Dorsa Sadat Kiaei 1 , Valerie Larouche 2 , Jean-Claude Décarie 3 , Uri Tabori 4 , Cynthia Hawkins 5 , sarah Lippe 3 , Benjamin Ellezam 3 , Luis H Ospina 3 , yves theoret 3 , Leandra Desjardins 3 , Marie-Elaine Metras 3 , serge Sultan 1 , Edith Cantin 6 , Marie-Eve Routhier 6 , Chantal Mailloux 3 , Marie-claude Bertrand 3 , Maxime Caru 7 , Tara McKeown 8 , Stephanie Vairy 9 , Geneviève Legault 10 , Eric Bouffet 11 , Vijay ramaswamy 11 , Hallie Coltin 3 , Lucie Lafay-Cousin 12 , Juliette Hukin 13 , Craig Erker 14 , Nada Jabado 15 , Mathieu Dehaes 16 , and Sébastien Perreault 17 ; 1 CHU Sainte-Justine, Montreal, Canada, 2 Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, Canada, 3 CHU Sainte-Justine, Montréal, Canada, 4 Hospital for Sick Children, Toronto, Canada, 5 Hospital for Sick Children, University of Toronto, Toronto, USA, 6 CHUL, Québec, Canada, 7 Penn State Cancer Institute, Hershey, USA, 8 SickKids, Toronto, Canada, 9 CHUS, Sherbrooke, Canada, 10 CUSM, Montréal, Canada, 11 Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada, Toronto, Canada, 12 Alberta Children's Hospital, Calgary, Canada, 13 BC Children's Hospital, Vancouver, Canada, 14 IWK Health Center, Halifax, USA, 15 The Research Institute of the McGill University Health Center, Montréal, Canada, 16 CHU Sainte-Justine, Montreal, Quebec, Canada, 17 Department of Neurosciences, CHU Sainte Justine, Montreal, Canada BACKGROUND: Plexiform neurofbromas (PN) are observed in up to 50% of patients with neurofbromatosis type 1 (NF1). Trametinib has been used widely to treat PN but limited data has been reported on its effcacy within a clinical trial. METHODS: This ongoing multicenter phase II trial includes patients with pediatric low-grade glioma and PN. Patients received daily oral trametinib (MEK inhibitor) for eighteen 28-day cycles. The volumes of PN were centrally quantifed using a new semi-automatic 3D segmentation method. RE- SULTS: As of May 15, 2022, 46 patients with PN were enrolled in the study and the recruitment was completed for this study arm. Thirty-four completed treatment and were available for analysis. For these patients, the median age was 10.5 years (range 0.7-19.8). The median volume of PN at baseline was 51cm 3 (range 2.6 to 487.6). Among the 34 patients, 28 (82.4%) completed 18 cycles as planned. Two patients discontinued due to adverse reaction, three patients refused to continue treatment and one patient discontinued treatment based on physician decision. Median duration of treatment was 16.8 months (range 2.8 to 16.8). Median duration of follow-up was 30.4 months (range 8.2 to 42).  A total of 38 PN were available for volumetric analysis. Using RECIST evaluation, the overall response rate was 13.1%. Volumetric assessment demon- strated an overall response rate of 64.7% (22/34 patients), and 65.8% (25/38 PN) of PN showed a decrease of more than 20% in volume. Median volume change was -30% (range -93.5 to 14.3). Thirty-one patients (91.1%) had dur- able response without progression (lasting ≥ 1 year). After discontinuation of treatment, one patient underwent surgery and three patients resumed MEK in- hibitor. CONCLUSION: We report outcome and volumetric quantifcation of PN treated with trametinib within a large clinical trial. Based on the current results, trametinib is effective and offers durable response. CTNI-05. MOLECULAR ANALYSIS OF THE PHASE I D-TERMINED TRIAL ON CONCURRENT AND ADJUVANT TEMOZOLOMIDE WITH MINOCYCLINE IN NEWLY DIAGNOSED HIGH-GRADE GLIOMA William McKean 1 , Kenneth Boucher 2 , Jingye Yang 3 , Karthik Sonty 3 , Randy Jensen 4 , Dennis Shrieve 5 , Karen Salzman 6 , Brett Johnson 3 , Melissa Thomas 3 , Whitney Moss 7 , Amanda Behunin 3 , Elizabeth Prystas 1 , Howard Colman 4 , and Adam Cohen 8 ; 1 Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA, Salt Lake City, UT, USA, 2 Division of Epidemiology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA, Salt Lake City, UT, USA, 3 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA, Salt Lake City, UT, USA, 4 Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA, Salt Lake City, UT, USA, 5 Department of Radiation Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA, Salt Lake City, UT, USA, 6 Division of Clinical Radiology, Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT, USA, Salt Lake City, UT, USA, 7 Division of Plastic Surgery, Department of Surgery, University of Utah, Salt Lake City, UT, USA, Salt Lake City, UT, USA, 8 Inova Schar Cancer Institute, UVA School of Medicine Inova Campus, Fairfax, VA, USA, Fairfax, VA, USA BACKGROUND: Minocycline blocks microglial TNF signaling and downstream NF-κB activation, which reduces the mesenchymal phenotype in preclinical models of GBM. Primary analysis of the D-TERMINED trial identifed a maximal tolerated dose (MTD) of oral minocycline at 150 mg Downloaded from https://academic.oup.com/neuro-oncology/article/24/Supplement_7/vii70/6826209 by guest on 17 November 2022