bluuebunny/crossref_metadata_2025_split huggingface dataset:
STEM-27. MECHANOSENSITIVE BRAIN TUMOR CELLS CONSTRUCT BLOOD-TUMOR BARRIER TO MASK CHEMOSENSITIVITY
Authors: Chen Xin , Momin Ali , Wanggou Siyi , Wang Xian , Dong Weifan , Fan Jerry , Sun Yu , Li Xuejun , Huang Xi 
Published: November 2022

Abstract
Two major obstacles in brain cancer treatment are the blood-tumor barrier (BTB) and quiescent tumor cells. Here we show that Sox2+ tumor cells directly project cellular processes to ensheathe capillaries in medulloblastoma (MB), a process that depends on the mechanosensitive ion channel Piezo2. MB develops a tissue stiffness gradient as a function of distance to capillaries. Sox2+ tumor cells perceive substrate stiffness to sustain local intracellular calcium, actomyosin tension, and adhesion to promote cellular process growth and cell surface sequestration of β-Catenin. Piezo2 knockout reverses WNT/β-Catenin signaling states between Sox2+ tumor cells and endothelial cells, compromises the BTB, reduces the quiescence of Sox2+ tumor cells, and markedly enhances MB response to chemotherapy. Our study reveals that mechanosensitive tumor cells construct the BTB to mask tumor chemosensitivity. Targeting Piezo2 addresses the BTB and tumor quiescence properties that underlie therapy failures in brain cancer.
RADT-11. CLINICAL OUTCOMES IN THE MANAGEMENT OF MELANOMA BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY AND ANTI-PD-1+CTLA-4
Authors: Tang Joseph , Dohm Ammoren , Kalagotla Hruday , Bhandari Menal , Kim Youngchul , Graham Jasmine , Khushalani Nikhil , Forsyth Peter , Etame Arnold , Liu James , Tran Nam , Vogelbaum Michael , Yu Michael , Ahmed Kamran , Oliver Daniel 
Published: November 2022

Abstract

BACKGROUND
Anti-PD-1+CTLA-4 therapy has revolutionized melanoma brain metastases (MBM) treatment. Prospective trials show higher response in asymptomatic versus symptomatic patients. We evaluated clinical outcomes in MBM treated with stereotactic radiosurgery (SRS) and anti-PD-1+CTLA-4.

METHODS
Patients were included if MBM were diagnosed and treated with SRS within 3 months of anti-PD-1+CTLA-4, and this was their last course of systemic treatment. Endpoints of this study were distant MBM control, MBM local control (LC) defined as less than 20% volume increase on follow-up MRI, and overall survival (OS) from SRS. Adverse advents were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

RESULTS
29 patients with 122 MBM treated over 40 SRS sessions between 2015-2020 were identified. Median SRS dose: 24 Gy (range: 15-24). Median MBM diameter: 0.6 cm (range: 0.3-2.9). Median follow-up using reverse Kaplan-Meier (KM) method: 19.3 months (interquartile range: 14.6-38.4).Six-, twelve-, and eighteen-month KM distant MBM control rates were 51%, 42%, 42%, respectively. LC rates: 90%, 86%, 85%. OS rates: 76%, 68%, 56%. 17 patients (59%) were asymptomatic and 12 (41%) symptomatic. KM distant MBM control and OS for asymptomatic and symptomatic patients were not significant; p=0.61 and p=0.67, respectively.On univariate analysis (UVA), Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) 0-1 was associated with increased risk of distant MBM failure versus DS-GPA 3.5-4 (hazard ratio (HR): 9.8, 95% confidence interval (CI) 1.9-51.5, p=0.007). UVA showed decreased OS with increased number of organs with metastases at diagnosis (HR:12, 95% CI 2.0-83.1, p=0.0075).2 lesions (1.6%) developed symptomatic radiation necrosis requiring steroids; 10 lesions developed grade 3 edema (8%); 13 patients experienced grade 1-2 fatigue and/or headache (45%); no patients experienced grade &gt;3 events.

CONCLUSION
Combination SRS and anti-PD-1+CTLA-4 in MBM shows durable intracranial control with similar outcomes between asymptomatic and symptomatic patients with acceptable toxicity. Further study is warranted.
RADT-29. THE IMPACT OF TUMOR LOCATION AT THE SKULL BASE ON RADIATION NECROSIS IN PATIENTS UNDERGOING STEREOTACTIC RADIOSURGERY: AN ANALYSIS OF 205 PATIENTS
Authors: Kerschbaumer Johannes , Demetz Matthias , Krigers Aleksandrs , Nevinny-Stickel Meinhard , Thomé Claudius , Freyschlag Christian 
Published: November 2022

Abstract

Background
Skull base (SB) surgery and radiosurgery (SRS) are an interdisciplinary concept and represent an individualized treatment option for various skull base tumors. Radiation necrosis (RN) is a possible sequela of SRS, but despite few accepted risk factors, there is very limited data on the influence of tumor location. The aim of this study was to assess tumor location in correlation to the development of radiation necrosis for skull-base tumors.

METHODS
All patients treated with radiosurgery for meningioma, vestibular schwannoma and other benign neoplasms between January 2004 and November 2020 were retrospectively evaluated. The clinical, imaging and medication data were gained from the patients’ charts. The diagnosis of RN was established retrospectively using imaging parameters. Patients with tumors located at the skull base were compared to patients with tumors of other location.

RESULTS
A total of 205 patients could be included in this study. 157 neoplasms (76.6%) were localized at the SB, while the remaining 48 (23.4%) were non-SB. 32 (15.6%) of all patients developed RN after median 10 (IqR 5-12) months during a median follow-up of 24 (IqR 6-62) months. SB-tumors showed a significantly lower risk of radiation necrosis with a Hazard Ratio (HR) of 0.252, p &lt; 0.001, independently of the applied radiation dose. Furthermore, higher radiation doses had a significant impact on the occurrence of RN (HR 1.372, p = 0.002). No significant difference could be shown for age, previous resection or previous radiosurgery. Administered dose of dexamethasone did not correlate with the risk of radiation necrosis.

CONCLUSION
The risk for development of RN for SB-tumors appears to be low. No difference between recurrent and newly diagnosed tumors was found, which may underpin the value of radiosurgical treatment for patients with recurrent SB-tumors. For extensive tumors of the SB, combinations of surgery and radiosurgery represents a valuable approach.
CTIM-05. FINAL RESULTS OF 2-THE-TOP: A PILOT PHASE 2 STUDY OF TTFIELDS (OPTUNE) PLUS PEMBROLIZUMAB PLUS MAINTENANCE TEMOZOLOMIDE (TMZ) IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM)
Authors: Tran David , Ghiaseddin Ashley , Chen Dongjiang , Le Son , Rahman Maryam 
Published: November 2022

Abstract

INTRODUCTION
TTFields induce anti-tumor immunity via type-1 interferon (T1IFN) pathways of the STING and AIM2 inflammasomes. Thus, TTFields may synergize with immune checkpoint inhibitors to prolong survival in GBM.

METHODS
We enrolled 26 ndGBM patients in a pilot phase 2 study combining TTFields, pembrolizumab and maintenance TMZ. Primary endpoints were PFS versus case-matched controls of TTFields plus TMZ in the EF-14 study and immune signatures by multiomics of PBMCs and tumors. Secondary endpoints included toxicity and OS.

RESULTS
The median age was 60.5 years. Fourteen (54%) had biopsy only or partial resection. Nineteen (73%) had unmethylated MGMT and 3 (11.5%) had an IDH mutation. As of 2/16/22, 7 (27%) were progression-free and 14 (54%) were alive with median follow-up of 16.8 months. Median PFS was 12.1 months versus 7.9 months in a case-matched control cohort of 26 patients (HR = 0.456; 95% CI: 0.222-0.937; P = 0.015). Twelve-month PFS was 52.4% (95% CI: 31.4-69.6%) versus 20.4% (95% CI: 5.5-41.7%) in controls; P = 0.012. Six of 15 (40%) patients with measurable disease achieved partial or complete response. Median OS was 25.2 months versus 15.9 months in controls (HR = 0.382; 95% CI: 0.168-0.861; P = 0.078). Two-year OS was 57.8% (95% CI: 33.7-75.9%) versus 19.2% (95% CI: 7.0-36.0%) in controls; P = 0.002. In a Cox regression analysis adjusting for key prognostic factors, P-value reached 0.033 for PFS and 0.020 for OS. Molecular analyses confirmed robust T cell activation via the T1IFN trajectory, which highly correlated with TCRαβ clonal expansion (Spearman coefficient = -0.8; P = 0.014), and defined a T cell-based gene signature of TTFields effects. The most common serious adverse events were thromboses, seizures, and metabolic disturbances in 4 (15%), 3 (11.5%), and 2 (8%) patients, respectively.

CONCLUSIONS
The triple combination demonstrated acceptable toxicity and promising efficacy in ndGBM. Survival and molecular data will be updated.
CTNI-11. DEEP PHENOTYPING OF MULTI DRUG RESPONSES IN PATIENTS WITH GLIOMAS USING TUMOR-EMBEDDED MICRODEVICES
Authors: Peruzzi Pierpaolo , Dominas Christine , Blitz Sarah , Chiocca E Antonio , Wen Patrick Y , Jonas Oliver 
Published: November 2022

Abstract
The lack of reliable predictive biomarkers to guide effective therapy is a major obstacle for the advancement of therapy for high grade gliomas (HGG), and particularly glioblastoma (GBM), one of the few cancers whose prognosis has not improved over the past several decades. With this pilot clinical trial we provide first in human evidence that drug-releasing intratumoral microdevices (IMD) can be safely and effectively used to obtain patient-specific, high throughput molecular and histopathological data to inform selection of drugs based on their observed antitumor effect in situ. The use of IMD is seamlessly integrated in standard surgical practice during tumor resection. None of the six enrolled patients experienced adverse events related to the IMD, and the retrieved tissue was usable for downstream analysis for 11 out of 12 retrieved specimens. Molecular analysis of the specimens provided, for the first time in humans, preliminary evidence of the robustness of the readout, with strong correlation between IMD analysis and clinic-radiological responses to temozolomide. From an investigational aspect, the amount of information obtained with IMD allows unprecedented characterization of tissue effects of any drugs of interest, within the physiological context of the intact tumor.
CTNI-19. A TWO-PART, PHASE 1 STUDY OF RHENIUM-186 NANOLIPOSOME (186RNL) DELIVERED BY CONVECTION ENHANCED DELIVERY (CED) FOR RECURRENT OR PROGRESSIVE CHILDHOOD EPENDYMOMA AND HIGH-GRADE GLIOMA (HGG)
Authors: Plant-Fox Ashley , DeCuypere Michael , Lam Sandi , Quijano Carla , Sereno Lisa , Bao Ande , LaFrance Norman , Hedrick Marc , Brenner Andrew 
Published: November 2022

Abstract
Childhood ependymoma and HGG are difficult tumors to treat. Recurrent ependymoma is treated with re-resection and multiple rounds of external beam radiation therapy (EBRT). HGG is treated with chemoradiation followed by clinical trials, if available. While EBRT remains a central component of management, it is limited by tolerance of the surrounding normal brain tissue. Rhenium-186 NanoLiposome (186RNL) permits the selective delivery of beta-emitting radiation with excellent tumor retention. In an adult Phase 1 trial for recurrent glioblastoma (NCT01906385), the mean absorbed dose to the tumor was 392 Gy (CI 306 – 478), markedly higher than absorbed doses typically delivered by EBRT. Despite this, no dose-limiting toxicity was observed and no treatment-related serious adverse events have occurred. Here, we describe the first pediatric trial using a two-part, Phase 1 dose-finding study followed by expansion cohorts to explore efficacy. Enrolling subjects will be 6 to 21 years of age with a diagnosis of recurrent ependymoma or HGG. Subjects will be allowed to enroll either if they have exhausted standard of care options or if they are clinically stable and surgical resection can be deferred by 4 weeks. Part 1 will enroll up to 24 subjects to determine the maximum feasible dose (MFD) of 186RNL administered by CED. Tumor size and concentration of infusate will be escalated in each cohort (A-D) to a maximum tumor diameter of 6 cm (114.1 mL) and a concentration of 2mCi/ml. Up to 4 CED catheters will be used. Part 2 will independently evaluate 186RNL in 2 different expansion cohorts: Cohort 2A: recurrent ependymoma; Cohort B: recurrent HGG. The primary endpoint for Cohort 2A is overall response rate (ORR) by Radiographic Assessment in Pediatric Neuro-Oncology (RAPNO) criteria and the primary endpoint for Cohort 2B is progression free survival. Planned enrollment will begin in early 2023.
CTNI-23. PRELIMINARY SAFETY AND PHARMACOKINETICS DATA FOR A PHASE 1B TRIAL OF TELAGLENASTAT IN COMBINATION WITH RADIATION THERAPY AND TEMOZOLOMIDE IN PATIENTS WITH IDH-MUTANT GRADE 2/3 ASTROCYTOMA (NCI-10218)
Authors: Kizilbash Sani , Piccioni David , Sahebjam Solmaz , Villano John , Jaeckle Kurt , Welch Mary , Kong Xiao-Tang , Holdhoff Matthias , Lammers Anita , Remick Adam , Reid Joel , Allred Jacob , Port John , Lanza Ian , McBrayer Samuel , Kunos Charles , Shapiro Geoffrey , Adjei Alex 
Published: November 2022

Abstract
IDH mutant gliomas depend on glutaminase for glutamate/glutathione generation from glutamine because R-2-hydroxyglutarate inhibits branched chain amino acid transaminase mediated glutamate biosynthesis. Telaglenastat (CB-839 HCl) is a potent glutaminase-1 specific inhibitor which depletes tumor glutamate in orthotopic IDH mutant glioma PDX models and extends survival in these orthotopic models when added to radiation/temozolomide. NCI-10218 (NCT03528642) is a phase I clinical trial investigating the safety and tolerability of telaglenastat administered orally concurrently with standard doses of radiation (50.4 Gy, grade 2; 59.4 Gy, grade 3) and temozolomide (75 mg/m2 orally daily) in patients (age 16+) with previously untreated IDH mutant grade 2/3 astrocytoma. Telaglenastat dose was escalated in cohorts (400-800 mg twice daily) based on a standard 3 + 3 design to determine the recommended phase 2 dose (RP2D). Toxicities were graded per CTCAE v5.0. An expansion cohort additionally incorporated a seven-day run-in of telaglenastat monotherapy at RP2D prior to radiation to evaluate the pharmacodynamic impact of telaglenastat on plasma and tumor metabolites. 23 patients with IDH mutant astrocytoma (WHO grade 2, n = 5; WHO grade 3, n = 18) were accrued between December 2018 and January 2022 (Dose Escalation: 16; Dose Expansion: 7). Median age was 32 years (range 23-69 years). 61% were male and 70% were ECOG 0. No dose-limiting toxicities were observed. Grade 3/4 adverse events (independent of attribution) included: lymphopenia (3), neutropenia (2), leukocytosis (2), alanine transaminase elevation (2), thrombocytopenia (1), leukopenia (1), maculopapular rash (1), hyperglycemia (1), hyponatremia (1). The RP2D of concurrent telaglenastat was defined as 800 mg twice daily. Following peak absorption on Day 15 at RP2D, the mean (%CV) terminal elimination half-life in the plasma was 4.2 (53.5%) hours (range 2.1-7.1 hours). The Cmax, Tmax, oral clearance, and AUC were 1496 ng/mL, 4.0 hr, 93.6 L/hr/m2, and 7430 ng/mL*hr, respectively.
CTNI-30. LOGGIC/FIREFLY-2: A PHASE 3, RANDOMIZED TRIAL OF TOVORAFENIB VS. CHEMOTHERAPY IN PEDIATRIC PATIENTS WITH NEWLY DIAGNOSED LOW-GRADE GLIOMA HARBORING AN ACTIVATING RAF ALTERATION
Authors: van Tilburg Cornelis , Jones David T , Schmidt Rene , Avula Shivaram , van Meeteren Antoinette Schouten- , Sehested Astrid , Opocher Enrico , Driever Pablo Hernáiz , Witt Ruth , Ziegler David , Blackman Samuel , Zhao Xin , Tsao Li-Pen , Cox Michael , Hargrave Darren , Witt Olaf 
Published: November 2022

Abstract

BACKGROUND
Genomic alterations and dysregulation of RAF are the main oncogenic driver in almost all pediatric low-grade gliomas (pLGGs). About 50%‒60% of pLGGs harbor KIAA1549-BRAF fusion and 5%‒15% BRAF V600E mutation. No targeted therapy has received regulatory approval for either relapsed or newly diagnosed pLGG to date. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II panRAF inhibitor. The registrational, phase 2 FIREFLY-1 (NCT04775485) study with tovorafenib in pediatric patients with recurrent/progressive LGG is currently ongoing.

METHODS
LOGGIC/FIREFLY-2 (EudraCT 2022-001363-27) is a registrational, randomized, multicenter, global (~100 sites across Australia, Canada, Egypt, Europe, New Zealand, Singapore, South Korea, Taiwan, and USA), phase 3 trial evaluating the efficacy, safety, and tolerability of tovorafenib vs. standard of care (SoC) chemotherapy in patients &lt; 25 years old with LGG harboring a RAF-alteration and requiring first-line systemic therapy. Approximately 400 patients will be randomized 1:1 to receive oral tovorafenib, 420 mg/m2 ( ≤ 600 mg) weekly (tablet or liquid suspension for 26, 28-day cycles), or an investigator’s choice of SoC chemotherapy: COG-V/C regimen (60 weeks), SIOPe-LGG-V/C (81 weeks) regimen, or single-agent vinblastine (70 weeks). After completing 26 cycles tovorafenib, patients may continue tovorafenib or opt to enter a drug holiday at any point. Patients who progress in the SoC arm may receive tovorafenib. Patients who progress after stopping tovorafenib may be re-challenged. Primary endpoint is ORR based on RANO criteria, as determined by an independent radiology committee. Key secondary endpoints are progression-free survival and duration of response per RANO criteria, and ORR per RAPNO criteria. Other secondary endpoints include changes in neurological and visual function, and safety and tolerability. Exploratory objectives include quality of life and health utilization measures, molecular biomarker evaluation for treatment response and resistance, efficacy of tovorafenib after progression on chemotherapy and retreatment upon progression during drug holiday.
CTNI-44. A PHASE 0 ‘TRIGGER’ TRIAL OF PAMIPARIB IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA PATIENTS
Authors: Sanai Nader , Chang Yu-Wei , Jiang Jun , Molloy Jennifer , Montgomery Chelsea , Harmon Jocelyn , Hong Amy , Wanebo John , Kennedy William , Garcia Michael , Barani Igor , Yoo Wonsuk , Tovmasyan Artak , Tien An-Chi , Li Jing , Mehta Shwetal 
Published: November 2022

Abstract
This study evaluates glioblastoma (GBM) pharmacokinetics (PK) and pharmacodynamics (PD) of pamiparib, a PARP1/2-selective inhibitor, graduating patients to a therapeutic expansion phase of drug plus radiotherapy. Newly-diagnosed (Arm A) and recurrent GBM (Arm B) patients received 4 days of pamiparib (60 mg BID) prior to planned resection at 2-4 or 8-12 hours following the final dose. Arm C included recurrent GBM patients who received 4 days of olaparib (200 mg BID). Tumor tissue cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’, defined as unbound drug &gt; 5-fold biochemical IC50 in nonenhancing tumor determined eligibility for the therapeutic expansion phase. PARP inhibition was assessed via ex vivo radiation and quantification of PAR levels compared to non-radiated control. All patients exceeding the PK threshold were eligible for an expansion phase of study drug plus radiotherapy followed by maintenance regimen. In Arms A (n = 20) and B (n = 15), the mean unbound concentrations of pamiparib in Gd-nonenhancing tumor region were 171.5 nM and 102.9 nM, respectively and in Arm C (n = 4) the mean unbound concentration of olaparib was 11.0 nM. All patients in Arms A and B, but only one in Arm C, exceeded the PK threshold to qualify for the expansion phase of the study. 12/20 (60%), 7/14 (50%), and 1/4 (25%) patients in Arms A, B, and C, respectively progressed to expansion phase. Radiation-induced PAR expression was 2.44 fold in untreated control vs 1.16 in Arm A, 0.82 in Arm B and 1.11 in Arm C patients, respectively. The median progression-free survival was 5.4 (Arm A) (n = 7), 5.0 months (Arm B) (n = 6), and 2.7 months (Arm C) (n = 1), respectively. Pamiparib was generally well-tolerated, achieved pharmacologically-relevant concentrations in nonenhancing GBM tissue and suppressed induction of PAR levels ex vivo post-radiation.
CTNI-47. TUMOR TREATING FIELDS COMBINE WITH TEMOZOLOMIDE FOR NEWLY DIAGNOSED GLIOBLASTOMA: A RETROSPECTIVE ANALYSIS OF CHINESE PATIENTS
Authors: Qin Zhiyong , Chen Lingchao , Chen Junrui , Yao Yu , Wu Jinsong , Zhuang Dongxiao , Nie Jigntao 
Published: November 2022

Abstract

BACKGROUND
TTFields plus Temozolomide (TTFields/TMZ) extended survival versus TMZ alone in newly diagnosed glioblastoma (GBM) patients in the EF-14 trial. We report a retrospective analysis of Chinese newly diagnosed GBM patients who received TTFields combine with TMZ treatment and traditional TMZ monotherapy from May 2019 to May 2021 in Shanghai Hua Shan hospital.METHOD: Overall survival (OS) and progression-free survival (PFS) curves were constructed using the Kaplan-Meier method. A Cox proportional hazards regression model with inverse probability of treatment weighting (IPTW) based on propensity score was used to assess the effect of TTFields and account for confounding factors. RESULT: In the preliminary analysis, the PFS in the TTFields/TMZ arm was 16 months (95% CI:9.6–24.6) versus 11 (95% CI: 9–12) with TMZ alone (p ＜0.05). Median overall survival was 21.8 months (95% CI 17.4-NA) with TTFields/TMZ versus 15 months (95% CI 13–18; HR 0.43, p ＜0.01) with TMZ alone. In the Multivariate analysis, Surgery type, STUPP scheme, IDH status, and TTFields use were identified as favorable prognostic factors. After PSM adjustment, the groups were similar, except that MGMT promoter methylation remained more in the TMZ group (12 v 32; P = 0.011). Upon IPTW Survival analysis, TTFields was associated with a significantly lower risk of death (hazard ratio [HR], 0.19 in OS (95% CI 0.09–0.41) and progression (HR, 0.35 (95% CI 0.14–0.91) compared with TMZ alone.

CONCLUSION
In the analysis of our single center of patients with glioblastoma, the addition of TTFields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone, resulted in statistically significant improvement in progression-free survival and overall survival. These results are consistent with the outcome of EF-14.
CTNI-53. PNOC014: PHASE IB STUDY RESULTS OF DAY101(TOVORAFENIB) FOR CHILDREN WITH LOW-GRADE GLIOMAS (LGGS) AND OTHER RAS/RAF/MEK/ERK PATHWAY-ACTIVATED TUMORS
Authors: Wright Karen , Kline Cassie , Abdelbaki Mohamed , Ebb David , Sayour Elias , Elster Jennifer , Leary Sarah , Miller Matthew , Margol Ashley , Cohen Kenneth , Kilburn Lindsay , Bendel Anne , Kao Pei-Chi , Ma Clement , London Wendy , Mueller Sabine , Prados Michael , Haas-Kogan Daphne 
Published: November 2022

Abstract

BACKGROUND
Pharmacokinetic modeling for previously reported phase 1A data of pan-RAF inhibitor DAY101 in RAS/RAF/MEK/ERK pathway-altered tumors suggested a correlation between higher doses and improved efficacy without clear safety data. The protocol was amended to explore differential dosing across different body surface areas (BSA).

METHODS
Eligible patients were &lt; 25 years old with radiographically recurrent/progressive RAS/RAF/MEK/ERK pathway-altered tumors. We applied a novel modification of a TITE-BOIN design to determine recommended phase 2 dosing of oral, weekly DAY101 in evaluable patients within two BSA subgroups: ≤ 1.5 m2 or &gt; 1.5 m2. Target toxicity probability was closest to 20%. We tested 420 and 530 mg/m2. Dose limiting toxicities (DLTs) were determined within Cycle 1. Evaluable patients had either ‘complete’ or ‘partial’ information. Complete information meant patient had a DLT or received 3 of 4 planned doses with no DLT. Partial information meant patient received only 1 or 2 doses or did not complete the DLT observation period. Three patients with complete information at a given dose level were required before dose escalation. The primary endpoint driving dose escalation was time from start of Cycle 1 to first DLT or, if no DLT, time from start of Cycle 1 to minimum of date of last contact or end of Cycle 1.

RESULTS
We treated 35 eligible patients: 21 KIAA1549:BRAF-, 9 BRAFV600E-, 4 novel RAF- and one FGFR1-altered tumors. Histologically, cohort included 30 LGGs, 4 high grade gliomas and 1 soft tissue sarcoma. There were 6 DLTs: 3 in each BSA subgroup, all at 530 mg/m2/dose, all grade 3, and 5 known side effects ( 2 fatigue, 3 rash, 1 menorrhagia).

CONCLUSIONS
Oral weekly DAY101 is well tolerated. The TITE model recommends 530 mg/m2/dose PO weekly for patients with BSA &lt; 1.5m2 and 420 mg/m2/dose PO weekly for patients with BSA &gt;1.5m2.