bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACTR-29. A SERIES OF PATIENTS (PTS) WITH RECURRENT GBM (rGBM) TREATED WITH ABT-414, BEVACIZUMAB (BEV) AND CCNU
Authors: De Silva Madhawa , Lee Adrian , Kastela Marina , Wheeler Helen , Khasraw Mustafa 
Published: November 2019

Abstract

BACKGROUND
ABT-414 showed encouraging results in the phase 2 Intellance 2 rGBM study, but not in the phase 3 Intellance 1 trial, in newly diagnosed EGFR-amplified GBM. We describe a series of pts with rGBM treated with ABT-414 in combination with Bev and CCNU.

METHODS
A retrospective review of pts with rGBM receiving ABT-414 with Bev and CCNU.

RESULTS
Between 3 and 10/2018, 6 male pts (median age 54y) with EGFR-amplified rGBM were given 1 mg/kg ABT-414 every 3 - 5 weeks (wk) in combination with 10 mg/kg Bev fortnightly. Two pts also received CCNU. Two pts had multifocal disease, and the remainder had left parietal, left frontal, occipital, and right frontal GBMs. All pts were IDH wild-type, and 5 out of 6 were MGMT-unmethylated. Four pts had upfront resection followed by adjuvant therapy, and received between 1 and 8 lines of therapy prior to ABT-414. Median time from chemoradiotherapy to ABT-414 was 34 wk. At time of abstract submission, median duration of therapy was 30 wk (range 5 – 64). Three pts were still alive, 1 on ABT-414 plus Bev, 1 on Bev alone (after ABT-414 + Bev), and 1 on best supportive care. Three pts died after 5, 17, and 42 wk, respectively. All pts developed ocular toxicities, manageable with dose reduction or delays, but no other grade 3 or 4 toxicities.

CONCLUSION
ABT-414 with Bev and CCNU was tolerable in this selected small series of pts with EGFR-amplified rGBM, and may have potential activity in selected patients, with 4 out of 6 pts (three MGMT-unmethylated) achieving a PFS greater than 27 wk (range 27 – 64). Despite the outcome of Intellance 1, there may be a subgroup of relapsed pts who benefit from this combination. Further studies are warranted to identify and analyse this group.
ACTR-34. SINGLE AGENT ONC201 IN PREVIOUSLY-TREATED, PROGRESSIVE ADULT H3 K27M-MUTANT GLIOMA
Authors: Arrillaga-Romany Isabel , Kurz Sylvia , Sumrall Ashley , Butowski Nicholas , Harrison Rebecca , DeGroot John , Chi Andrew , Sulman Erik , Shonka Nicole , Umemura Yoshie , Odia Yazmin , Mehta Minesh , Iwamoto Fabio , Leia Nghiemphu P , Cloughesy Timothy , Tarapore Rohinton , Merdinger Krystal , Oster Wolfgang , Allen Joshua , Batchelor Tracy , Lassman Andrew , Wen Patrick 
Published: November 2019

Abstract
H3 K27M-mutant gliomas often manifest as midline gliomas, have a dismal prognosis, and have no established or effective treatments at recurrence. ONC201 is the first clinical bitopic DRD2 antagonist/ClpP agonist and is under evaluation in Phase II trials for gliomas and other cancers. We previously reported in vitro studies suggesting dysregulated dopamine receptor expression and enhanced ONC201 sensitivity among H3 K27M-mutant gliomas. Following these observations, adults with midline H3 K27M-mutant glioma patients were enrolled to a dedicated Phase II clinical trial (NCT03295396), a multi-arm Phase II trial (NCT0252569), and expanded access protocols under the Sponsor’s IND. An integrated radiographic analysis with an objective response rate primary endpoint in patients who received ONC201 monotherapy with confirmed H3 K27M-mutant glioma (not primarily in the pons or spinal cord and without leptomeningeal spread) that was progressive and measurable disease by RANO criteria, >90 days from completion of prior radiation, and had KPS >60. As of December 15, 2018, 15 patients have received single agent ONC201 who meet these criteria (n=9 NCT03295396; n=5 NCT0252569; n=1 expanded access). ONC201 was orally administered at 625 mg weekly, except for one patient dosed once every 3 weeks. As midline gliomas can exhibit a mixture of contrast-enhancing and non-contrast-enhancing disease, objective response was assessed by blinded independent central review using RANO-HGG and RANO-LGG criteria for each patient. Best response to date by RANO-HGG criteria is at least 27%: 1 CR, 3 PR, 7 SD, and 4 PD; by RANO-LGG is at least 36%: 1 CR, 1 PR, 3 minor response (MR), 4 SD, 5 PD, 1 unevaluable. By RANO-HGG, median onset of response is 2.6 months (range 1.3–3.4); median duration of response has not been reached with a median follow-up of 7.7 months (range 1.8–29.8). Updated radiographic response, pharmacodynamics, safety, and other clinical outcomes will be reported.
ACTR-35. A STUDY OF RACE AND SOCIOECONOMIC STATUS IMPACTING THERAPEUTIC CLINICAL TRIAL ENROLLMENT IN ADULT GLIOMAS PATIENTS
Authors: Morshed Ramin , Reihl Sheantel , Kakaizada Sofia , Zhang Eric , Young Jacob , Clarke Jennifer , Butowski Nicholas , Taylor Jennie , Ann Oberheim-Bush Nancy , Aghi Manish , Berger Mitchel , Chang Susan , Hervey-Jumper Shawn 
Published: November 2019

Abstract

OBJECT
Under-enrollment in clinical trials significantly limits valid analyses of clinical interventions and generalizability of findings. Often it results in premature study termination, with estimates of 22% to 50% of clinical trials terminated due to poor accrual. Currently, there are limited reports addressing the influence of race/ethnicity and socioeconomic status on clinical trial enrollment in patients with adult glioma. The goal of this study was to determine if these factors impact clinical trial participation for glioma patients.

METHODS
852 adult patients were identified from the UCSF Tumor Board Registry and analyzed to determine the rate of therapeutic clinical trial consideration, tumor board recommendation, and study enrollment based on clinical reports in their electronic medical records.

RESULTS
At initial diagnosis, 30.7% and 18.0% of glioma patients were recommended and enrolled in a therapeutic clinical trial, respectively. At recurrence, 38.7% and 25.3% of patients were recommended and enrolled in a clinical trial, respectively. Nineteen percent of the study population belonged to a NIH-designated underrepresented minority group; Asian/Pacific-Islander comprising 10.3% overall. On univariate analysis, only in-state location, distance to the hospital, and WHO grade were associated with consideration, recommendation, and enrollment at initial diagnosis and recurrence. Minority status, insurance type, median household income, and percent below poverty were not associated with clinical trial recommendation or enrollment.

CONCLUSION
Race and socioeconomic status did not impact clinical trial consideration, tumor board recommendation, or study enrollment. Our results do not support the premise that provider decisions are impacted by biases based on minority or socioeconomic status.
ACTR-44. FEASIBILITY, PHARMACODYNAMICS, AND BIOLOGIC ACTIVITY OF THE GLIOMA ATKINS-BASED DIET (GLAD) FOR PREVENTING TUMOR RECURRENCE IN GLIOMA PATIENTS
Authors: Schreck Karisa , Hsu Fang-Chi , Berrington Adam , Henry-Barron Bobbie J , Blair Lindsay , Hartman Adam , Kossoff Eric , Easter Linda , Self Mary , Whitlow Chris , Barker Peter , Cervenka Mackenzie , O Blakeley Jaishri , Strowd Roy 
Published: November 2019

Abstract

INTRODUCTION
Exploiting metabolic vulnerabilities via ketosis is a promising approach for gliomas. The modified Atkins diet is a ketogenic diet therapy efficacious in adults with refractory epilepsy. We evaluated the feasibility, pharmacokinetics/pharmacodynamics(PK/PD), and cerebral activity of this dietary intervention intended to induce ketosis.

METHODS
25 patients with biopsy-confirmed WHO Grade 2–4 astrocytoma with stable disease after adjuvant chemotherapy were enrolled in an 8-week GLioma Atkins-based Diet (GLAD). GLAD consisted of 2 ‘intermittent fasting’ days(IF; calories < 20% of recommended daily allowance) interleaved between 5 modified-Atkins diet days(MAD; carbohydrates < 20 gm/day) each week. The primary outcome was dietary compliance. Secondary outcomes were PK assessed by urine ketones post-FAST and post-MAD, PD assessed by serum insulin and IGF-1, and cerebral activity measured by MR spectroscopy at baseline and week 8.

RESULTS
Grade 2(n=2;8%), Grade 3(n=11;44%) and GBMs(n=12;48%) were enrolled. While only 48% of participants satisfied pre-defined compliance criteria, overall compliance with MAD(80%) was higher than IF(72%). Weight loss was observed (-4.8 + 2.2kg,p< 0.0001) consisting primarily of decreased fat mass (-2.5 + 3.1%,p< 0.0001), with increased lean body mass (2.4 + 3.2%,p< 0.0001), stable nutritional status (phase angle, -0.26 + 0.94%,p=0.22), and normalization of BMI. Urine acetoacetate significantly increased with 55% achieving moderate ketosis at week 8 (p=0.0005). Serum insulin and IGF-1 significantly decreased indicating systemic dietary response and were associated with higher ketones post-IF, but not post-MAD. MRS demonstrated cerebral activity with increased ketones in lesional (0.06±0.03- >0.27±0.06i.u,p=0.005) and contralateral brain at week 8 (0.041±0.01- >0.16±0.04i.u.,p=0.004). Higher cerebral acetone correlated with higher urine ketones (r >0.75,p< 0.02) and lower fasting glucose (r >-0.74,p< 0.05).

CONCLUSIONS
The GLAD diet was challenging to maintain but demonstrated quantifiable biologic effects systemically and intratumorally. MAD was more feasible than IF, but changes in PD markers correlated most strongly with IF. The role of ketogenic diet therapy for preventing glioma growth remains uncertain.
ACTR-46. TUMOR TREATING FIELDS COMBINED WITH RADIOTHERAPY AND TEMOZOLOMIDE FOR THE TREATMENT OF NEWLY DIAGNOSED GLIOBLASTOMA: FINAL RESULTS FROM A PILOT STUDY
Authors: Grossman Rachel , Limon Dror , Bokstein Felix , Blumenthal Deborah , Ben Harush Camit , Ram Zvi 
Published: November 2019

Abstract

BACKGROUND
Tumor Treating Fields (TTFields) are a non-invasive, loco-regional, anti-mitotic treatment comprising low intensity alternating electric fields approved for GBM. Preclinical data show that TTFields have a radio-sensitizing effect. This pilot study evaluated the safety and feasibility of TTFields/RT/TMZ in ndGBM patients.

METHODS
Patients with histologically confirmed ndGBM were treated with TTFields/RT/TMZ followed by maintenance TTFields and TMZ for up to 24 months. TTFields (200kHz) were delivered for >18 hours/day with removal of the transducer arrays during RT delivery. TMZ was administered at 75 mg/m2/daily for 6 weeks and RT at a total dose of 60 Gy. The primary endpoint was safety of the combined TTFields/RT/TMZ; secondary endpoints included progression-free survival (PFS), overall survival (OS) and toxicity. Adverse events (AEs) were graded per CTCAE V4.0.

RESULTS
Ten patients were enrolled at a single center in Israel between April and December 2017. All patients had recovered from maximal debulking surgery or biopsy. Five patients (50%) had undergone gross total resection; rest had biopsy only. Median age was 59 and median KPS was 80. Median dose of RT was 60 Gy. Six patients (60%) reported at least one AE. The most common AE was TTFields-related skin toxicity reported in 4 patients (40%), of Grade 1–2 in severity. Two patients reported serious AEs (seizures and general deterioration) considered unrelated to TTFields. Median PFS with RT/TMZ/TTFields was 10.5 months. Median OS has not been reached.

CONCLUSIONS
The proportion of patients with TTFields-related skin toxicity was similar to that reported in EF-14 phase 3 study (52%). No other TTFields-related toxicities were reported. There was no increase in RT- or TMZ-related toxicities with TTFields/RT/TMZ combination. A phase 2 randomized study has been initiated to investigate the efficacy of concomitant RT/TMZ/TTFields in 60 ndGBM patients.
ACTR-52. PHASE 1 STUDY OF FT-2102, AN INHIBITOR OF MUTANT IDH1, IN PATIENTS WITH RELAPSED/REFRACTORY IDH1 MUTANT GLIOMAS: PRELIMINARY SAFETY AND CLINICAL ACTIVITY
Authors: De la Fuente Macarena I , Colman Howard , Rosenthal Mark , Van Tine Brian A , Fonkem Ekokobe , Walbert Tobias , Milhem Mohammed , Lipford Kate , Forsyth Sanjeev , Guichard Sylvie , Brevard Julie , Mikhailov Yelena , Thomson Blythe , Monga Varun 
Published: November 2019

Abstract

BACKGROUND
Isocitrate dehydrogenase mutations (mIDH1) are present in > 70% of patients with Grade II/III gliomas resulting in production and accumulation of (R)-2-hydroxyglutarate causing DNA hypermethylation and promoting tumorigenesis. FT-2102 is a potent, brain penetrant (Kpuu=0.4 in intact rodent) and selective inhibitor of mIDH1.

METHODS
Patients with advanced relapsed/refractory mIDH1 gliomas received FT-2102 150mg BID, orally. Following a dose confirmation 3 + 3 Phase 1b, 20 pts enrolled in a Simon 2 stage Phase 2 study (NCT: 03684811).

RESULTS
As of 01-May-2019, 23 with glioma (Grade at enrollment: II/III/IV; n=4, n=12 & n=7 respectively) were treated with FT-2102 monotherapy. The patient’s median age was 46 years (range: 23–64) & 61% were male. Median number of prior treatments was 2 (range 1–5) and 78% had received prior temozolomide. mIDH1 status was locally determined (IHC, NGS or PCR): R132H, R132L, R132C & unspecified (n=15, n=2, n=1 & n=5). Median duration of FT-2102 treatment to date was 40 days (range: 26–177), with 1 patient discontinuing (disease progression). Treatment emergent adverse events (all grades, regardless of attribution) that occurred in >10% of were: fatigue (22%), nausea (17%), diarrhea (17%), ALT increase (13%), headache (13%) and AST increase (13%), none leading to treatment discontinuation. None experienced an adverse event of QTcF prolongation or skin hyperpigmentation. There were no protocol-defined DLT’s. To date, six had at least 1 evaluable post-baseline response assessment, with best response of 1 PR (unconfirmed as of data cutoff), 3 SD and 2 PD. Responses of patients remaining on FT-2102 will be updated as available. Evaluations of serum/CSF pharmacokinetics and selected pharmacodynamics will be provided.

CONCLUSION
FT-2102 at 150 mg BID demonstrates acceptable safety and tolerability with potential clinical activity in with gliomas. The Phase 2 study is ongoing, evaluating both single agent, FT-2102 and in combination with azacitidine.
ACTR-53. MGMT PROMOTER METHYLATION ANALYSIS FOR ALLOCATING COMBINED CCNU/TMZ CHEMOTHERAPY: LESSONS LEARNED FROM THE CeTeG/NOA-09 TRIAL
Authors: Tzaridis Theophilos , Schäfer Niklas , Weller Johannes , Steinbach Joachim , Seidel Sabine , Schlegel Uwe , Sabel Michael , Hau Peter , Seidel Clemens , Krex Dietmar , Goldbrunner Roland , Tonn Joerg-Christian , Grauer Oliver , Schaub Christina , Coch Christoph , Glas Martin , Pietsch Torsten , Fimmers Rolf , Reifenberger Guido , Felsberg Jörg , Herrlinger Ulrich 
Published: November 2019

Abstract

BACKGROUND
The CeTeG/NOA-09 trial recently showed a survival benefit for combination chemotherapy with CCNU/TMZ in glioblastoma patients with a methylated MGMT promoter as determined by quantitative Methylation-Specific PCR (qMSP). Identifying patient subgroups with a pronounced benefit from this novel treatment is crucial. Here, we report on the prognostic and predictive value of MGMT promoter methylation ratio determined by qMSP and investigate the concordance of pyrosequencing (PSQ) and qMSP for patients in this trial.

METHODS
qMSP and PSQ were used for MGMT promoter methylation analysis. The mITT population of the CeTeG/NOA-09 trial was used for multivariate analysis including the parameters MGMT promoter methylation ratio, RPA class and study center.

RESULTS
Patients of the mITT population of the CeTeG/NOA-09 trial (n=129) with MGMT promoter methylation ratio greater than 4 (qMSP) showed a superior overall survival compared to patients with borderline methylation ratio of 2–4 (p=0.0251). In the latter patients, treatment with CCNU/TMZ did not show a survival benefit (p=0.924). Multivariate analysis with treatment arm, RPA class and study center as covariates did not confirm a prognostic or predictive value of MGMT promoter methylation ratio (qMSP) for patients of the mITT population (n=129, HR=0.88; 95% CI: 0.72 – 1.08) or patients with a ratio greater than 4 (n=117, HR =0.86; 95% CI: 0.69 – 1.07). In a subset of 49 trial patients, qMSP and PSQ showed not only a high qualitative (45/49; 91.8%), but also a high quantitative concordance rate (Spearman correlation, r=0.83, p< 0.0001).

CONCLUSION
Glioblastoma patients with borderline MGMT promoter methylation (qMSP ratio 2–4) do not seem to benefit from combination treatment with CCNU/TMZ. Thus, we propose a qMSP cut-off of 4 as a novel decision tool for clinicians. qMSP and PSQ show a high concordance rate indicating that a decision for combination therapy can also be based on PSQ results.
ACTR-57. A PHASE 1/2 STUDY TO EVALUATE THE SAFETY AND EFFICACY OF BLOOD-BRAIN BARRIER (BBB) OPENING WITH A NINE-EMITTER IMPLANTABLE ULTRASOUND DEVICE IN RECURRENT GLIOBLASTOMA PATIENTS PRIOR TO CARBOPLATIN
Authors: Idbaih Ahmed , Ducray François , DeGroot John , Stupp Roger , Guyotat Jacques , Lesniak Maciej S , Sonabend Adam , Weinberg Jeffrey , Desseaux Carole , Canney Michael , Schmitt Charlotte , Carpentier Alexandre 
Published: November 2019

Abstract
The blood-brain barrier (BBB) limits penetration of systemically administered therapies to brain tumors and peritumoral tissue and may be responsible for the failure of numerous drugs in recent clinical trials for glioblastoma (GBM). Low intensity pulsed ultrasound (LIPU), with concomitant intravenous microbubble injection (DEFINITY®), can temporarily disrupt the BBB for 6–24 hours and allow for enhanced delivery of drugs to the brain. In previous clinical studies, a 1-cm ultrasound (US) device, SonoCloud-1, was implanted in a burr hole of recurrent GBM patients (n=27) and used to disrupt the BBB prior to carboplatin infusion at AUC5. This ongoing pilot phase 1/2 study (NCT03744026) aims to evaluate the safety and efficacy of transient opening of the BBB by LIPU in rGBM with the SonoCloud-9, a larger nine-emitter implantable device, designed to cover the tumor and surrounding infiltrative regions. The ultrasound device is implanted in a 6 cm x 6 cm bone flap window after tumor debulking surgery. Patients receive a 270-second sonication every month with concomitant microbubble injection to disrupt the BBB followed by carboplatin infusion at AUC4-6. Magnetic resonance imaging (MRI) is performed to verify safety and extent of BBB disruption. This study began enrollment in early 2019 and is an international, open-label, single arm, multi-site, dose-escalation and expansion trial to evaluate the safety of escalating sonication volume (“dose”) with concurrent carboplatin. The number of activated emitters in the implant (3, 6, 9) is increased using a 3 + 3 dose escalation design. Safety data of the escalation phase of the study will be presented.
ACTR-58. BASELINE REQUIREMENTS FOR NOVEL AGENTS BEING CONSIDERED FOR BRAIN CANCER EFFICACY TRIALS: REPORT OF AN ABTC WORKSHOP
Authors: Grossman Stuart , Romo Carlos , Rudek-Renaut Michelle , Supko Jeffrey , Fisher Joy , Nabors Burt , Wen Patrick , Peereboom David , Ellingson Benjamin , Ye Xiaobu 
Published: November 2019

Abstract
Despite advances in the understanding of molecular pathways, the availability of NGS panels to identify potentially drugable mutations, the proliferation of targeted therapies, and the progress seen in other cancers, only one novel agent (temozolomide) has significantly improved the survival of patients with glioblastoma in the past three decades. A major factor distinguishing brain cancer from other malignancies is the presence of the blood-brain barrier that restricts entry into the central nervous system of over 95% of drugs currently approved by the FDA. Clinical investigators have historically justified glioblastoma efficacy trials with pharmacokinetic data documenting measurable brain concentrations in animals or in contrast enhancing brain tumor specimens from patients. However, the discovery of effective therapeutic agents (whose mechanism of action requires that the drug directly reaches the cancer) will likely require that therapeutic drug concentrations (rather than measurable levels or blood:brain ratios) be delivered to non-contrast enhancing regions of the brain. The importance of delivering therapeutic concentrations of drug to non-enhancing brain is highlighted by knowledge that a gross total resection of all enhancing portions of a glioblastoma provides no chance of cure and limited improvement in overall survival. Utilizing these more stringent emerging criteria to select novel agents for efficacy studies will encourage pre-clinical and phase I studies to define the CNS penetration of new drugs and determine a therapeutic concentration for each agent. This will aid in the rational prioritization of agents selected for phase II studies. A full report of the outcome of the ABTC workshop on this topic will be presented. This will include: 1) methods to determine “therapeutic” drug concentrations for glioblastoma, 2) methods to quantify drug concentrations in non-enhancing brain, 3) pharmacokinetic and pharmacodynamic considerations, and 4) potential shortcomings of this approach.
STEM-27. LEVERAGING FUNCTIONAL GENETIC DEPENDENCIES IN TREATMENT-REFRACTORY GLIOBLASTOMA
Authors: Chokshi Chirayu , Tieu David , Brown Kevin , Venugopal Chitra , Kuhlmann Laura , Ignatchenko Vladimir , Tong Amy , Chan Katherine , Savage Neil , Subapanditha Minomi , McKenna Dillon , Lazo John , Kislinger Thomas , Moffat Jason , Singh Sheila 
Published: November 2019

Abstract
As the most common primary brain tumor in adults causing death, Glioblastoma (GBM) remains a therapeutic challenge. Unchanged for almost two decades, standard therapy is ineffective at preventing disease relapse with a median patient survival of < 15 months. Stem cell-like subpopulations of tumor cells, known as brain tumor initiating cells (BTICs), evade standard therapy and lead to relapse. Whereas previous studies largely focus on pre-treatment primary GBM (pGBM), we conducted a panel of genome-wide CRISPR-Cas9 gene knockout screens to determine modulators of treatment resistance and de novo genetic vulnerabilities arising at disease recurrence. Using our in vitro model of conventional therapy, we identified genes modulating sensitivity and resistance to Temozolomide and/or radiation therapy in patient-derived pGBM BTICs. Genes modulating sensitivity belong to Fanconi anaemia nuclear complex, interstrand cross link repair, and regulation of stem cell maintenance and differentiation. Following in vitro validation of gene knockouts conferring treatment sensitization in multiple pGBM BTIC lines, we continued to conduct the first genome-wide CRISPR-Cas9 screens in patient-derived rGBM BTICs. Focusing on genetic vulnerabilities arising de novo at disease relapse, we introduce the context-specific role of protein tyrosine phosphatase 4A2 (PTP4A2) in rGBM. Genetic knockout or small molecule targeting of PTP4A2 leads to a context-specific vulnerability of rGBM self renewal capacity and in vivo tumorigenecity. To continue our analysis of treatment-refractory GBM and overcome intertumoral heterogeneity, we conducted genome-wide CRISPR-Cas9 gene knockout screens and whole cell proteomics on patient-matched pGBM and rGBM BTICs. With >1000 differentially essential genes, combined functional genetic and proteomic analyses implicates genes involved in mRNA splicing, nucleotide metabolism, and activation of gene expression by sterol regulatory element-binding protein. Together, our functional genetic approach elucidates novel genes regulating treatment resistance and disease recurrence in GBM.