bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiative lifetimes, branching fractions, and oscillator strengths of high-lying levels in Re I
Authors: Li Yongfan , Gamrath Sébastien , Palmeri Patrick , Quinet Pascal , Li Qiu , Yu Qi , Zhang Meiqi , Zhou Lina , Dai Zhenwen
Published: November 2019

Radiative lifetimes of 19 levels in Re I were measured using the time-resolved laser-induced fluorescence method. As far as we know, 15 results are reported for the first time. By combining the experimental lifetimes determined from the present work with theoretical branching fractions obtained by a pseudo-relativistic Hartree–Fock model including core-polarization contributions, a new set of semi-empirical transition probabilities and oscillator strengths for 47 Re I lines from 18 newly measured levels were derived.
Structure of an RNA aptamer in complex with the fluorophore tetramethylrhodamine
Authors: Duchardt-Ferner Elke , Juen Michael , Bourgeois Benjamin , Madl Tobias , Kreutz Christoph , Ohlenschläger Oliver , Wöhnert Jens
Published: November 2019

RNA aptamers—artificially created RNAs with high affinity and selectivity for their target ligand generated from random sequence pools—are versatile tools in the fields of biotechnology and medicine. On a more fundamental level, they also further our general understanding of RNA-ligand interactions e. g. in regard to the relationship between structural complexity and ligand affinity and specificity, RNA structure and RNA folding. Detailed structural knowledge on a wide range of aptamer–ligand complexes is required to further our understanding of RNA–ligand interactions. Here, we present the atomic resolution structure of an RNA–aptamer binding to the fluorescent xanthene dye tetramethylrhodamine. The high resolution structure, solved by NMR-spectroscopy in solution, reveals binding features both common and different from the binding mode of other aptamers with affinity for ligands carrying planar aromatic ring systems such as the malachite green aptamer which binds to the tetramethylrhodamine related dye malachite green or the flavin mononucleotide aptamer.
ATIM-21. THE CURRENT STATUS OF AD-SGE-REIC GENE THERAPY FOR MALIGNANT GLIOMA
Authors: Kurozumi Kazuhiko , Fujii Kentaro , Oka Tetsuo , Shimazu Yosuke , Hattori Yasuhiko , Tomita Yusuke , Uneda Atsuhito , Matsumoto Yuji , Tsuboi Nobushige , Kaneda Keisuke , Makino Keigo , Michiue Hiroyuki , Kumorn Hiromi , Date Isao
Published: November 2019

INTRODUCTION

Expression of the gene encoding reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) was reported to be reduced in a variety of human cancer cells. We previously examined the antitumor effect of an adenoviral vector carrying REIC/Dkk-3 gene (Ad-CAG-REIC). Recently, a novel adenoviral vector expressing REIC/Dkk-3 has also been developed based on the cytomegalovirus promoter-driven super gene expression system (Ad-SGE-REIC). We evaluated the anti-glioma effect of the Ad-SGE-REIC and planned a clinical trial of Ad-SGE-REIC for malignant glioma.

MATERIALS AND METHODS

We evaluated a cytotoxicity assay to treatments with Ad-SGE-REIC, Ad-CAG-REIC, or Ad-LacZ (control) using malignant glioma cells. The survival of mice in each group was analyzed by the Kaplan–Meier method. We also performed Good Laboratory Practice (GLP) toxicology tests and prepared a protocol for this clinical trial.

RESULTS

In the cytotoxicity assay, after treatment with Ad-SGE-REIC, the number of malignant glioma cells attached to the bottom of culture wells was significantly reduced in a time-dependent manner. Mice treated with Ad-SGE-REIC survived significantly longer than those treated with other vectors. We also performed GLP toxicology tests using intracranial injection of higher doses of Ad-SGE-REIC in rats at Shin Nippon Biomedical Laboratories (SNBL Japan) to determine the injection dose of Ad-SGE-REIC for this clinical trial. After finishing the consultation with Pharmaceuticals and Medical Devices Agency (PMDA), we prepared a protocol for a phase I/IIa clinical trial of Ad-SGE-REIC for the treatment of recurrent malignant glioma supported by Japan Agency for Medical Research and Development (AMED). This protocol was reviewed by institution review board (IRB) in March 2019. We submitted a notification of this trial in April 2019.

CONCLUSIONS

We demonstrated the anti-glioma effect of Ad-SGE-REIC. We will start a phase I/IIa clinical trial of Ad-SGE-REIC for the treatment of recurrent malignant glioma.
ATIM-23. PRELIMINARY FINDINGS OF A PHASE I SAFETY AND BIOIMAGING TRIAL OF KB004 (IFABOTUZUMAB) IN PATIENTS WITH GLIOBLASTOMA
Authors: Gan Hui , Cher Lawrence , Inglis Po , Lwin Zarnie , Lau Eddie , Ackermann Uwe , Coombs Nicole , Remen Kirsten , Guo Nancy , Ting Lee Sze , Gong Sylvia , Palmer Jodie , Pathmaraj Kunthi , O’Keefe Graeme , Scott Fiona , Day Bryan , Boyd Andrew , Thomas Paul , Durrant Cameron , Scott Andrew
Published: November 2019

Glioblastoma (GBM) is the most frequent and lethal primary brain neoplasm. EphA3 is a tumor restricted antigen expressed in 38–40% of GBM and 100% of the tumor vasculature. Ifabotuzumab is a non-fucosylated IgG1κ antibody targeting EphA3 receptor. A Phase 1 study of ifabotuzumab in haematological malignancies was well tolerated and clinically active. Here we report on a Phase I dose escalation and biodistribution study of ifabotuzumab in recurrent glioblastoma. DESIGN The primary objective is to determine the toxicity 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. Eligible pts 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, frequency of in situ EphA3 expression and tumor uptake. Safety and PK assessments were undertaken. On Day 8, pts commenced weekly ifabotuzumab infusions until PD. Three cohorts are planned (3.5mg/kg, 5.25 mg/kg, 7.9 mg/kg). On day 36, pts received both 89Zr-ifab and Ifabotuzumab, to assess receptor occupancy. Response rate (RANO) and survival data were collected. RESULTS: To date, 7 of 12 pts have enrolled (6 at 3.5 mg/kg,1 at 5.25 mg/kg; Mean age: 55 years (±12.6), 4 are male). Treatment emergent AEs included infusion reactions, seizures, cerebral oedema, rash, pruritis, headaches, eye disorder. Most were considered related to study drug, seizures and infusion reactions were readily managed with increased premedications after the first occurrence. Best response in cohort 1 is SD for 23 weeks. 89Zr-ifab PET/CT scans showed rapid, specific targeting at all known tumor sites and in all pts, but no normal tissue uptake. MRI scans showed predominant T2/FLAIR changes, occasionally marked, which were consistent with treatment effect on tumor vasculature.
ATIM-26. INTERIM RESULTS OF THE EXTENSION PHASE OF A PHASE I/IIA TRIAL OF A THERAPEUTIC CMV VACCINE AGAINST RECURRENT GLIOBLASTOMA (GBM)
Authors: Wen Patrick , Reardon David , Lee Eudocia , Iwamoto Fabio , Anderson David , Diaz-Mitoma Francisco , Lassman Andrew
Published: November 2019

Cytomegalovirus (CMV) antigens have been reported in over 90% of GBM tumors. CD4+and CD8+T cells are most frequently directed against the gB and pp65 antigens, respectively, and are immunogenic targets in a CMV-based GBM vaccine. We have initiated a phase I/IIa clinical trial for patients with recurrent GBM using gB/pp65 enveloped virus-like particles (eVLPs) formulated with GM-CSF and administered intradermally. In phase I, eligible patients were age 18–70 with Karnofsky Performance Status at least 70, normal end-organ function, on stable or decreasing corticosteroids of at most 4mg dexamethasone (or equivalent), with recurrent GBM following any standard initial therapy and any number of recurrences of any size. Patients were vaccinated monthly until tumor progression, with immune-monitoring performed 2 weeks after each vaccination and MRI exams every 6 weeks. The primary endpoint was safety/tolerability and secondarily to assess immunogenicity. Three vaccine doses (0.4µg, 2µg, and 10µg pp65) were evaluated with 6 patients in each cohort, and the DSMB identified no DLTs or safety concerns with any of the doses. The highest 10µg dose was chosen for the Phase IIa extension phase of the trial based on stable disease (3 months or longer) observed in 3/6 patients, which correlated with vaccine-induced IFN-γ-secreting T cell responses against CMV. Enrollment in phase IIa of the trial, which is designed to explore initial potential efficacy signals in an additional 10 patients that receive the optimal 10µg dose of vaccine, is expected in June 2019 and includes the additional requirements of unifocal, measurable enhancing tumor 1–3 cm across at first recurrence and no prior immunotherapy. Patients will be vaccinated monthly until clinical progression. Tumor responses and associated immunological biomarkers will be presented, and are expected to include initial data for all 10 patients.
ATIM-31. SAFETY OF TUMOR-SPECIFIC PEPTIDE VACCINE TARGETING ISOCITRATE DEHYDROGENASE 1 MUTATION IN RECURRENT RESECTABLE LOW GRADE GLIOMA PATIENTS
Authors: Peters Katherine , Congdon Kendra , Archer Gary , Woodring Sarah , Jaggers Denise , Lipp Eric , Healy Patrick , Herndon James , Soher Brian , Vlahovic Gordana , Johnson Margaret , Randazzo Dina , Desjardins Annick , Friedman Henry , Friedman Allan , Ashley David , Yan Hai , Sampson John
Published: November 2019

BACKGROUND

Low grade gliomas (LGGs) represent 10–15% of glial tumors in adults and while LGG patients have a better prognosis over high-grade gliomas, these cancers ultimately recur and transform to more aggressive tumors. Isocitrate dehydrogenase 1 (IDH1) is commonly mutated in LGG, and when mutated, it is the oncogenic driver by leading to the production of oncometabolite 2-hydroxyglutarate (2-HG). We developed a phase 1 study for recurrent resectable IDH1 mutant LGG utilizing a tumor-specific peptide vaccine targeting IDH1 mutant protein that spans the mutated region of IDHR132H (PEPIDH1M vaccine).

METHODS

We performed a phase 1, single-center, clinical trial in recurrent resectable IDH1 mutant WHO grade II glioma patients. Subjects received three PEPIDH1M vaccine q2wks and then proceeded to surgical resection. If subject’s tumor retained grade II status, then the subject proceeded with 12 cycles of daily TMZ (50 mg/m2 X 28 days) and PEPIDH1M vaccine (12 injections q4wks). If subject’s tumor transformed to grade III, then subject proceeded to radiation therapy (RT) with concurrent TMZ followed by 12 cycles of daily TMZ (50 mg/m2 X 28 days) and PEPIDH1M vaccine (12 injections q4wks). Primary endpoint was safety of PEPIDH1M vaccine in combination with adjuvant TMZ and/or XRT/TMZ and evaluable subjects needed to receive ≥6 PEPIDH1M vaccines. We assessed safety using CTCAE 4.03.

RESULTS

We enrolled 24 recurrent LGG subjects with mean age of 43.8 yrs (sd=11.4 yrs). Twenty subjects completed ≥6 PEPIDH1M vaccines. Most common related toxicity was grade 1 injection site reaction (N=20) and skin induration (n=17) with no grade 3–4 related toxicities.

CONCLUSIONS

PEPIDH1M vaccine in combination with surgical resection, daily TMZ and/or RT + TMZ with daily TMZ was safe and well tolerated in recurrent IDH1 mutant LGG. We are currently exploring secondary/correlative endpoints including immunogenicity of PEPIDH1M vaccine and magnetic resonance spectroscopy for 2-HG.
ATIM-47. NIVOLUMAB VS BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA: EXPLORATORY ANALYSIS OF MGMT METHYLATION STATUS AND BASELINE CORTICOSTEROID USE
Authors: Weller Michael , Reardon David , Brandes Alba , Sampson John , Mulholland Paul , Wick Antje , Baehring Joachim , Ahluwalia Manmeet , Roth Patrick , Bähr Oliver , Phuphanich Surasak , Sepulveda Juan , de Souza Paul , Sahebjam Solmaz , Potter Von , Tatsuoka Kay , Taitt Corina , Zwirtes Ricardo , Omuro Antonio , Lim Michael
Published: November 2019

BACKGROUND

Current therapies for recurrent glioblastoma provide limited survival benefit. In the open-label, phase 3 CheckMate 143 study (NCT02017717), although the primary endpoint was not met, the median overall survival (mOS) was comparable between nivolumab (anti–PD-1) and bevacizumab in the overall population of patients with glioblastoma at first recurrence after temozolomide chemoradiotherapy (Reardon et al, WFNOS 2017). Exploratory subgroup analyses were conducted to evaluate the association of O-6-methylguanine DNA methyltransferase (MGMT) promoter methylation status and corticosteroid use at baseline with mOS.

METHODS

Prespecified patient subgroups included MGMT promoter status (methylated vs unmethylated) and baseline corticosteroid use (yes [within 5 days of first dose] vs no). FINDINGS: Methylation status was available for 102/184 (55%) nivolumab-treated and 109/185 (59%) bevacizumab-treated patients. Using a multivariable Cox proportional hazards model analysis, no baseline corticosteroid use (HR, 0.59 [95% CI, 0.36–0.95]) and methylated MGMT status (HR, 0.47 [95% CI, 0.29–0.78]) were each associated with longer mOS among nivolumab-treated patients. Among patients with methylated MGMT and no baseline corticosteroid use, mOS was 17.0 months with nivolumab (n=31) and 10.1 months with bevacizumab (n=22; HR, 0.58 [95% CI, 0.30–1.11]). In patients with methylated tumors and baseline corticosteroids, mOS was 7.7 months with nivolumab (n=12) and 13.5 months with bevacizumab (n=17). Among patients with unmethylated tumors and no baseline corticosteroids, mOS was 8.3 months with nivolumab (n=30) and 10.3 months with bevacizumab (n=29). In patients with unmethylated tumors and baseline corticosteroids, mOS was 5.6 months with nivolumab (n=28) and 8.3 months with bevacizumab (n=28).

CONCLUSION

A trend toward longer mOS with nivolumab was observed in a subgroup of patients with methylated MGMT and no baseline corticosteroid use. These findings suggest that MGMT methylation status and corticosteroid use at baseline could be used to identify patients who may benefit from nivolumab and thus warrant further study.
ACTR-13. FINAL RESULTS WITH CHEMORADIOTHERAPY FOR ANAPLASTIC OLIGODENDROGLIAL TUMORS FROM NRG ONCOLOGY/RTOG 9402
Authors: Lassman Andrew , Won Minhee , Gregory Cairncross J , Shaw Edward , Ashby Lynn , Souhami Luis , Laack Nadia , Fink Karen , Macdonald David , Bahary Jean-Paul , Hartford Alan , Whitton Anthony , Werner-Wasik Maria , Laperriere Normand , Suh John , Robinson Clifford , Mehta Minesh
Published: November 2019

BACKGROUND

Adding intensive-procarbazine, lomustine, and vincristine (iPCV) to radiotherapy (RT) prolonged progression-free (PFS) and overall survival (OS) for patients with 1p19q codeleted anaplastic oligodendroglial tumors (AOTs); some benefit was also observed for IDH-mutant non-codeleted cases (Cairncross et al 2013, 2014, 2016). Now, 25 years after study activation, we updated survival, further assessed IDH as a predictive biomarker, and are exploring the benefit from vincristine.

METHODS

Eligible adults (KPS ≥ 60, adequate end-organ function) were randomized to pre-RT iPCV (4 cycles x 6 weeks each) vs. RT alone, stratified by age (< or ≥ 50), KPS (60–70 or ≥ 80), and level of anaplasia. Histology (anaplastic oligodendroglioma/oligo-astrocytoma required) and biomarkers (IDH and 1p19q, post-hoc) were determined centrally. Survival was estimated by Kaplan-Meier and Hazard Ratios (HRs) by Cox-regression.

RESULTS

Overall (n=289), median follow-up was 16.4 years vs. 11.3 years at last report. In codeleted cases, 40% randomized to iPCV remained alive vs. 53% at last report; 5, 10, and 14 year-PFS and -OS rates were 62%, 50%, 41% and 70%, 57%, 46%, respectively; and iPCV unequivocally prolonged PFS (median 9.8 vs. 2.9 years, HR 0.46, 95% CI 0.3–0.7, p< 0.001) and OS (median 13.2 vs. 7.3 years, HR 0.61, 95% CI 0.40–0.94; p=0.02). With IDH mutation but without codeletion (n=66), iPCV prolonged PFS (median 2.8 vs. 1.9 years, HR 0.58, 95% CI 0.34–0.99, p=0.046); OS was longer with a trend for significance (median 5.5 vs. 3.3 years, HR 0.6, 95% CI 0.34–1.03, p=0.06) on this underpowered exploratory post-hoc analysis.

CONCLUSION

For codeleted AOTs, long-term analyses confirmed that pre-RT iPCV produced meaningful and significant prolongations of PFS and OS. With IDH mutation but without codeletion, iPCV significantly prolonged PFS and showed a trend for prolonged OS. The value of vincristine is being assessed. Supported by NCI grants U10CA180868, U10CA180822, U24CA196067, and UG1CA189867.
ACTR-19. REPORT ON THE COMBINATION OF AXITINIB AND TUMOR TREATING FIELDS (TTFIELDS) IN THREE PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Schulz Ellina , Kessler Almuth F , Weiland Judith , Linsenmann Thomas , Ernestus Ralf-Ingo , Hagemann Carsten , Löhr Mario
Published: November 2019

OBJECTIVE

Tumor Treating Fields (TTFields) significantly improved survival of newly diagnosed glioblastoma (ndGBM) patients in the EF-14 trial. Axitinib is an orally available tyrosine kinase inhibitor which is approved for the treatment of metastatic renal cell carcinoma. It has a high affinity and specificity for vascular endothelial growth factor receptors. In phase 2 trials, Axitinib improved response rate and PFS in recurrent GBM (rGBM) patients with a manageable toxicity profile. Here, three rGBM patients treated with TTFields and Axitinib (AxiTTFields) are presented.

PATIENT SECTION

A 53-year-old male patient (#1) presented with a progressing GBM after initial surgery, radiochemotherapy followed by 4 cycles of temozolomide (TMZ) and TTFields. In a 46-year-old male patient (#2), early progress occurred after surgery, radiochemotherapy and 3 cycles of TMZ combined with TTFields. In both patients Axitinib was added to the treatment regimen to meet the urgent need of an alternative treatment. In a 61-year-old male patient (#3) with rGBM after surgery, radiochemotherapy and 6 cycles of TMZ, TTFields therapy was initiated at recurrence and the treatment regimen was adapted to AxiTTFields.

RESULTS

No additional adverse events due to the combined therapy of AxiTTFields were observed. Patients #1 and #2 were on AxiTTFields therapy for more than 8 months, presenting an improved neurological status with a partial response in the MRI 3 months after initiating AxiTTFields. #3 declined in his neurological status without any change in the MRI monitoring and died 2.4 months after initiating AxiTTFields. With an average of 77%, the TTFields usage rate was above the independent prognostic threshold of 75%, underlining the feasibility of this approach.

CONCLUSION

AxiTTFields was feasible and safe in three rGBM patients. The addition of Axitinib to TTFields therapy is a promising approach and safety/feasibility will be further investigated in a pilot trial.
ACTR-27. EVOLUTION OF THE NEUROSURGEON’S ROLE IN CLINICAL TRIALS FOR GBM: A SYSTEMATIC OVERVIEW OF THE CLINICALTRIALS.GOV DATABASE
Authors: Mansouri Alireza , Beyn Michelle , Pancholi Aditya , Chow Clement , Boutet Alexandre , Elias Gavin , Germann Jurgen , Zadeh Gelareh
Published: November 2019

BACKGROUND

The therapeutic challenge of glioblastoma (GBM) has catalyzed the active pursuit of a high volume of clinical trials to evaluate novel interventions for this deadly disease. Our enhanced understanding of the biology of GBMs has translated into an evolution of the role of the neurosurgeon as well. In this study, we have evaluated the current landscape of surgical clinical trials in GBM to characterize this evolution, describe current trends, and identify potential gaps in methodological features.

METHODS

The ClinicalTrials.gov database was searched for surgical/procedural trials in individuals with GBM on May 14th, 2019 without date limitations. Demographics, specific intervention (e.g. technical, device use, or local drug delivery), phase, sample size, and main outcome measures were abstracted.

RESULTS

270 of 2140 trials (12.6%) were identified as procedural. The majority were based in the USA (189/270, 70%), single-center (188/270, 70%), and not randomized by design (215/270, 80%). Primary and recurrent GBMs were evenly addressed. Industry-funding supported 106/270 (39%) of studies. The leading test intervention was local delivery of therapeutics (44.8%), followed by use of novel devices (33%). Surgical technique/procedures comprised 20%. Early Phase designs predominated (177/270, 65.5%) but 67 (24.8%) did not report Phase. The greatest surge in new registrations over the last decade was seen in Phase I trials. The top primary outcome was safety/tolerability/ feasibility (107/270, 39%), followed by survival (62/270, 22%); 35 (12.6%) did not report a primary outcome. Approximately 15% of studies were terminated, withdrawn or suspended. Only 6 records were associated with reported results.

CONCLUSIONS

In GBMs, procedural interventions comprise a notable proportion of trials. Local delivery of therapeutics and novel device applications, predominantly through Phase I designs, represent the evolved role of the neurosurgeon in neuro-oncology. Improved documentation of design, outcomes, and reporting of results are needed to better inform the field and increase efficiency.
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

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

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

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

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

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

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

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

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

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

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.
STEM-28. TARGETING KIF11 TO RADIOSENSITIZE GLIOBLASTOMA
Authors: Zalenski Abigail , Montgomery Miranda , De Kuntal , Grubb Treg , Venere Monica
Published: November 2019

Glioblastoma (GBM) is the most common primary brain tumor, and is incredibly lethal, with less than 10% of patients surviving more than 5 years after diagnosis. These tumors are routinely treated with radiotherapy, although we and others have shown that there is a subpopulation of GBM cells, called cancer stem-like cells (CSCs), that are radio-resistant, and do not respond to this standard therapy. We aim to overcome the radio-resistance of GBM CSCs by using radiotherapy in combination with a KIF11 inhibitor. We previously reported that the mitotic kinesin KIF11, required for bipolar spindle formation during mitosis, is elevated in GBM and portends poor prognosis. We also demonstrated that invasiveness and self-renewal of CSCs could be targeted with ispinesib, a small molecule inhibitor to KIF11. Furthermore, survival of mice bearing orthotopic glioblastoma was prolonged with KIF11 inhibition, although tumor burden increased with cessation of treatment. To combat tumor recurrence after treatment cessation, we proposed to use a KIF11 inhibitor with radiotherapy. KIF11 inhibitors will arrest cells in G2/M, where they are most sensitive to radiotherapy. By enriching CSCs in G2/M, we hypothesized that we would overcome CSC radio-resistance to decrease CSC viability and improve survival. We first tested the efficacy of combining a KIF11 inhibitor and irradiation in vitro. We found that using combination therapy to treat CSCs significantly decreased CSC survival over vehicle or either treatment used as a monotherapy. We then investigated the effects of combination therapy in vivo. Using a KIF11 inhibitor combined with irradiation increased survival of mice bearing orthotopic glioblastoma. Our results suggest that targeting KIF11 in combination with radiotherapy is a promising technique to overcome the radio-resistance of CSCs, and holds potential to significantly improve treatment outcomes and extend survival of patients with GBM.