bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pediatric and young adult phase I dose escalation study of BXQ-350 for solid and central nervous system tumors.
Authors: Abdelbaki Mohamed , Setty Bhuvana , DeWire Mariko Dawn , Cripe Timothy P. , Curry Richard 
Published: May 2020

2541 Background: BXQ-350 is a novel agent composed of the multifunctional, lysosomal activator protein Saposin C (SapC) and dioleoyl- phosphatidylserine (DOPS) and has demonstrated antitumor effects in both in vitro and in vivo preclinical models. Many tumors, including high-grade glioma and diffuse intrinsic pontine glioma (DIPG), and cells of tumor vasculature have aberrantly exposed phosphatidylserine (PS)-rich domains on the cell surface. BXQ-350 is an anti-tumor agent in development from Bexion Pharmaceuticals, Inc. that selectively targets tumor cell PS, particularly those translocated to the outer leaflet of the plasma membrane in tumor cells. BXQ-350 activates and participates in various cellular processes, including apoptosis and necrosis, and may also exhibit novel mechanisms leading to cell death that require further investigation. Methods: Nine refractory solid (2) and central nervous system (7) tumor patients (5F:4M, age 4-23 years of age) were enrolled in a 2-site dose escalation phase I first-in-pediatric trial ( NCT03967093 ) which completed in 2019. All patients received at least one dose of BXQ-350 which was administered as an intravenous infusion. Dosing began at 1.8 mg/kg and escalated to the highest planned dose level of 3.2mg/kg. Results: There were no BXQ-350-related serious adverse events, dose limiting toxicities, or withdrawals. The highest planned dose of 3.2 mg/kg was achieved safely but a maximum tolerated dose was not established. One osteosarcoma patient had progressive disease prior to completing cycle one of treatment and was removed from trial. Eight patients (DIPG-3, HGG-1, GBM-1, Pineoblasotoma-1, Ependymoma-1, Osteosarcoma-1) completed at least one cycle, with one DIPG patient completing cycle five. Conclusions: BXQ-350 was well tolerated with no significant dose-limiting toxicities at the highest planed dose level. A pediatric phase I trial in newly diagnosed patients is planned for 2nd quarter 2020. Clinical trial information: NCT03967093 .
Phase I study of BPM31510 and vitamin K in patients with high grade glioma recurrent after a bevacizumab-containing regimen.
Authors: Nagpal Seema , Thomas Reena Parada , Bertrand Sophie , Yerraballa Hari Priya , Iv Michael , Li Gordon , Klotz Alison , Kiebish Michael A. , Narain Niven R. , Sarangarajan Rangaprasad , Granger Elder , Recht Lawrence David 
Published: May 2020

2543 Background: BPM31510 is an ubidecarenone-lipid conjugate nanodispersion in clinical development for advanced malignancies, including high grade glioma (HGG). BPM31510’s anti-cancer effect is mediated by induction of mitochondrial superoxide and activation of cell death in glioblastoma models. Herein, we present preliminary pharmaco-kinetic and dynamic data, and survival from a phase I study of BPM31510 + Vitamin K in HGG with progression after bevacizumab (BEV). Methods: This was an open-label phase I study of BPM31510 continuous infusion with Vitamin K (10mg IM qweek) using a mTPI design, starting at 110mg/kg 2X/week, allowing 2 dose escalations & 1 de-escalation. Patients had received ChemoRT and were in recurrence after BEV. Results: Of 12 patients treated with BPM31510, 9 completed the 28-day DLT period. 2 patients came off study for progressive disease; 1 patient after asymptomatic hemorrhage into tumor bed (G1). 10 patients had primary GB, 2 had AA. Median age was 54.5yo (27-67) and KPS 70 (60-90). On Day 1 of BPM31510, a dose dependent increase in Cmax was observed; Tmax values were similar for all doses. AUC was linear with dose escalation. For all doses, Day 4 Cmax values were higher compared to Day 1. In contrast there was variable decrease in Tmax (table). Of evaluable patients, 4 patients received the highest dose 171mg/kg, where a single patient experienced DLT: G3 AST & ALT. The most common grade 1/2 AEs were elevated AST, rash, and fatigue, each occurring in 4 patients. The mOS for 9 eligible/evaluable patients was 128 days (95% CI: 48-209) while PFS was 34 days (95% CI of mean 8.9). Two patients are currently alive >12 months. Conclusions: BPM31510 + vitamin K demonstrated a safe profile to maximum dose of 171mg/kg twice/week with potential therapeutic utility in treatment-refractory HGG patients. Multi-omic molecular profiles characterizing AE and response to be reported from the study will be investigated for next phase of clinical development. Clinical trial information: NCT03020602 . [Table: see text]
Impact of lymphopenia on survival for elderly patients with glioblastoma: A secondary analysis of the CCTG CE.6 (EORTC 26062-22061, TROG03.01) randomized clinical trial.
Authors: Song Andrew Jehyun , Ding Keyue , Laperriere Normand , Perry James R. , Mason Warren P. , Winch Chad , O'Callaghan Christopher J. , Menten Johan , Brandes Alba Ariela , Phillips Claire , Fay Michael F. , Nishikawa Ryo , Osoba David , Cairncross Gregory , Roa Wilson , Wick Wolfgang , Shi Wenyin 
Published: May 2020

2547 Background: Lymphopenia (LMP) may lead to worse outcomes for patients with glioblastoma (GBM). This study is a secondary analysis of the CCTG CE.6 trial evaluating the impact of chemotherapy and radiation on LMP, as well as the association of LMP with overall survival. Methods: CCTG clinical trial CE.6 randomized elderly GBM patients (≥ 65 yrs) to short course radiation alone (RT) or short course radiation with temozolomide (RT + TMZ). In this study LMP (mild-mod: grade 1-2; severe: grade 3-4) was defined per CTCAE v3.0 criteria, and measured at baseline, 1 wk and 4 wks post-RT. Pre-selected key factors for the analysis included age, sex, ECOG, extent of resection, MGMT methylation, MMSE, and steroid use. Multinomial logistic regression models were used to identify factors associated with LMP and multivariable Cox regression models were used to study effect of LMP on survival. Results: A total of 562 patients were included for analysis (281 RT vs 281 RT+TMZ). At baseline, both arms (RT vs RT+TMZ) had similar rates of mild-mod (21.4% vs 21.4%) and severe (3.2% vs 2.9%) LMP. The 1 wk post-RT LMP rates were also similar (p = 0.25). However, RT+TMZ pts were more likely to develop both mild-mod LMP (18.2% vs 27.9%) and severe LMP (1.8% vs 9.3%) [p < 0.001] at 4 wks post-RT. Developing mild-mod and severe LMP post-RT were both associated with baseline LMP (p < 0.001) and RT+TMZ (p < 0.001). Severe LMP at 4 wks post-RT was also associated with biopsy only (p < 0.02). After adjusting for confounding factors, 4 wks post-RT LMP was not significantly associated with PFS or OS regardless of severity. However, baseline LMP (HR 1.3) was significantly associated with worse OS (HR: 1.30, 95% C.I.: 1.05-1.62, p = 0.02), regardless of MGMT status. Other factors significantly associated with worse outcome included: males (HR 1.41), biopsy only (HR 1.59), and lower MMSE (HR 1.03). Conclusions: Short course RT alone does not lead to LMP after treatment. Development of LMP post-RT is associated with addition of TMZ and baseline LMP. However, only baseline LMP is associated with worse OS regardless of MGMT status. This may be considered as a prognostic biomarker for elderly GBM patients and warrants further validation. Clinical trial information: NCT00482677 .
Escalation portion of phase II study to evaluate the safety, pharmacokinetics, and clinical activity of the PI3K/mTOR inhibitor paxalisib (GDC-0084) in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status.
Authors: Wen Patrick Y. , De Groot John Frederick , Battiste James D. , Goldlust Samuel Aaron , Garner James Stuart , Simpson Jeremy Andrew , Kijlstra Jelle , Olivero Alan , Cloughesy Timothy Francis 
Published: May 2020

2550 Background: Paxalisib (previously GDC-0084) is a potent, oral, selective, brain-penetrant, small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin. The PI3K pathway is upregulated in ~85% of GBM cases and paxalisib has shown efficacy in preclinical models. A phase I study (NCT01547546) investigated paxalisib dosed once daily in 47 patients with recurrent high-grade gliomas and established a maximum tolerated dose (MTD) of 45mg once daily. The current phase Il study aims to explore the safety, tolerability, and clinical activity of paxalisib in newly diagnosed GBM and an unmethylated MGMT promotor following surgery and temozolomide chemoradiation per Stupp regimen. Methods: Part 1 of this study is an open-label, dose-escalation phase to assess the safety, tolerability and MTD. Dose-escalation started at 60mg and progressed in 15mg increments using a 3+3 design. Part 2 is an expansion cohort recruiting 20 patients randomized to administration in fed or fasted states at the MTD. Results: Part 1 is complete and reported here. Nine patients were recruited and an MTD of 60mg was determined. DLTs were hyperglycemia and oral mucositis. AEs were generally reversible and consistent with the PI3K inhibitor class with the most common events were rash, oral mucositis, and fatigue. PK at the MTD was broadly consistent with the data published for the phase 1 study. For eight response-evaluable patients in Part I the median progression-free survival (PFS) was 8.4 months, and 25% of patients remained progression free after 15 months of follow-up. Part 2 is ongoing. Conclusions: A higher MTD of 60mg was identified in newly diagnosed GBM with unmethylated MGMT promotor status than the 45mg MTD previously identified in recurrent high-grade glioma. An encouraging PFS signal is described in this poor-prognosis, unmethylated MGMT patient population. Clinical trial information: NCT03522298 .
Evaluation of glioblastoma tumor microenvironment after treatment with pembrolizumab.
Authors: Majd Nazanin , Lin Heather Y. , Yuan Ying , Alfaro-Munoz Kristin , Hunter Kathy , Heimberger Amy B. , De Groot John Frederick 
Published: May 2020

2559 Background: Neoadjuvant pembrolizumab improved outcome of patients with recurrent Glioblastoma (GBM) in two early phase clinical trials. However, several large phase II/III studies in patients with newly diagnosed and recurrent GBM failed to demonstrate a therapeutic benefit of anti-PD-1 therapy. Therefore, identification of biomarkers of response is crucial for appropriate patient selection and further clinical development of anti-PD-1 therapy. We reported the outcome of our window-of-opportunity clinical trial of neoadjuvant pembrolizumab in 15 patients with recurrent GBM, demonstrating rare CD8+ T cells and abundant of CD68+ macrophages in GBM tissue after 3 weeks of anti-PD-1 treatment (NCT02337686). In the current study, we compared tumor infiltrating lymphocyte (TIL) and PD-L1 scores, known biomarkers of response to anti-PD-1 therapy in other cancers, in pre-trial vs. on-trial tumor tissue and associated these markers with survival. Methods: We determined TIL score (morphological assessment of the presence or absence of TILs, 0-3) and PD-L1 H score (defined as [1*1+ %]+[2*2+ %]+[3*3+ %], 0-200) and correlated these with survival. The Wilcoxon signed rank test was used to compare levels of PD-L1 H or TIL scores between pre-trial and on-trial specimens. The Cox proportional hazards models were used to assess associations between correlative markers and progression free survival or overall survival (OS). Results: The on-trial TIL level (median: 3) was significantly higher than the pre-trial TIL level (median: 1) (p = 0.031). However the difference between pre-trial and on-trial PD-L1 levels was not statistically significant (p > 0.9). Patients whose on-trial PD-L1 H score was ≥ 3 trended toward a longer OS than those with a PD-L1 H score < 3 (HR [95% CI] = 0.225 [0.043, 1.183]) (p = 0.0782). Conclusions: Although GBM tissue lacks abundant T cells, treatment with pembrolizumab increases trafficking of T cells to the tumor microenvironment, which is necessary but not sufficient to induce an effector T-cell response. Elevated PD-L1 expression may be a biomarker of response to anti-PD1 therapy in GBM, which needs confirmation in larger studies. Further genomic, transcriptomic, and methylation profiling of the pre-trial and on-trial tissues is ongoing. Clinical trial information: NCT02337686 .
Phase I trial of D2C7 immunotoxin (D2C7-IT) administered intratumorally via convection-enhanced delivery (CED) for recurrent malignant glioma (MG).
Authors: Desjardins Annick , Randazzo Dina , Chandramohan Vidyalakshmi , Peters Katherine B. , Johnson Margaret O , Threatt Stevie , Bullock Chevelle A , Herndon James Emmett , Healy Patrick , Lipp Eric S , Sampson John H. , Friedman Allan H. , Friedman Henry S. , Ashley David M. , Bigner Darell D. 
Published: May 2020

2566 Background: D2C7-IT is a recombinant immunotoxin comprised of a dual-specific antibody fragment targeting EGFRwt and EGFRvIII and a genetically engineered form of the Pseudomonas exotoxin, PE38-KDEL. We report the results of a phase I trial evaluating D2C7-IT delivered intratumorally by CED. Methods: Eligible patients were adults with recurrent supratentorial WHO grade III or IV MG; solitary tumor; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS>70%. Two patients per dose level (DL) were to enroll in the dose escalation portion (dose range: 40ng/mL to 23,354ng/mL). Results: From May 2015 to May 2018, 43 patients enrolled on study. Observed dose limiting toxicities include: grade 4 seizure (n=1) on DL3, grade 3 confusion and pyramidal tract syndrome (n=1) on DL13, and grade 4 cerebral edema (n=1) and grade 3 dysphasia (n=1) on DL17. Grade 3 or higher adverse events possibly related to D2C7-IT include: seizure (grade 4, n=2; grade 3, n=3), cerebral edema (grade 4, n=1), hydrocephalus (grade 3, n=5), headache (grade 3, n=4), hemiparesis (grade 3, n=4), dysphasia (grade 3, n=3), lymphopenia (grade 3, n=4), thromboembolic event (grade 3, n=3); and one each of grade 3 elevated ALT, urinary tract infection, fall, wound complication, generalized muscle weakness, confusion, encephalopathy, and somnolence. As of February 2020, four patients remain alive, with three patients demonstrating persistent radiographic partial response more than 54, 34 and 28 months after a single infusion of D2C7-IT. Conclusions: Dose level 13 (6,920ng/mL) was selected as the optimal phase II dose. Accrual in a dose expansion phase II trial is ongoing, and we are initiating a combination trial of D2C7-IT with checkpoint inhibitior. Clinical trial information: NCT02303678 .
Intratumoral drug distribution of adavosertib in patients with glioblastoma: Interim results of phase I study.
Authors: Romo Carlos G , Alexander Brian Michael , Agar Nathalie , Ahluwalia Manmeet Singh , Desai Arati Suvas , Dietrich Jorg , Kaley Thomas Joseph , Peereboom David M. , Takebe Naoko , Desideri Serena , Fisher Joy D. , Sims Megan , Ye Xiaobu , Ligon Keith L. , Nabors Louis B. , Wen Patrick Y. , Grossman Stuart A. , Supko Jeffrey G. , Lee Eudocia Quant 
Published: May 2020

2568 Background: Wee1 is a key regulator of the G2/M checkpoint and is frequently overexpressed in glioblastoma (GB). Adavosertib is a first-in-class oral, small molecule inhibitor of Wee1 that acts primarily as a DNA damage sensitizer. A phase I clinical trial was conducted to evaluate its safety and establish the recommended phase II dosing. Studies were undertaken to evaluate whether potentially therapeutic concentrations of the drug are achieved in recurrent tumor and adjacent non-enhancing brain regions with presumed intact blood-brain barrier (BBB). Methods: Twelve patients received five daily doses of adavosertib pre-operatively at either the maximum tolerated dose (MTD) for concurrent radiation or adjuvant temozolomide. Tissue from contrast enhancing (CE) and non-enhancing (NE) brain regions was obtained for analysis during surgical resection. A second stage is being conducted using microdialysis (MD) to facilitate continuous sampling of extracellular fluid (ECF) and measuring free drug concentrations in: normal-appearing brain, contrast enhancing tumor, and a peritumoral T2 hyperintense area. The concentration of total adavosertib in plasma and tissue homogenates and free drug in ECF were determined by validated LC/MS/MS methods. Results: Geometric mean concentrations of adavosertib after a 200 mg dose were 644 ng/mL and 119 ng/mL in CE and NE tissue specimens, respectively (6 patients). At the 425 mg dose, the mean concentrations were 3,576 ng/mL in CE tissue and 885 ng/mL in NE tissue (6 patients). MD was performed in 2 patients. Samples from functional MD catheters were collected from NE brain in patient no. 1 and from two NE areas and a FLAIR hyperintense region in patient no. 2, with the following results in the table. Conclusions: The total drug concentration in tissue samples was notably lower in regions of the brain with a relatively intact BBB as compared to contrast enhancing tissue. Concentrations of adavosertib measured by MD vary markedly depending on catheter location. Free drug levels in ECF within brain with a functional BBB, although considerably lower than total drug levels in tissue, were 2-10 times below the previously reported IC50 for antiproliferative activity against sensitive GB cell lines (127 ng/mL). Whether or not the target of the drug is effectively inhibited at these concentrations remains to be demonstrated. Clinical trial information: NCT01849146 . [Table: see text]
Pilot study on outcome and antitumor efficacy of an autologous cancer cell vaccine applied in patients with advanced solid tumors.
Authors: Gonzalez Marcano Eglys , Kröhle Leona , Ahlers Joachim , Drevs Joachim 
Published: May 2020

3000 Background: In the last decade cancer immunotherapy has emerged as the most promising anti-tumor approach. The most commonly used immunotherapies are vaccines and checkpoint inhibitors. An autologous cell vaccine is made with the patient's own tumor cells processed in vitro, which may elicit a cytotoxic T-lymphocytic immune response against tumor cells antigens, resulting in tumor cell death. We performed a pilot study to evaluate the clinical relevance and general outcome of an autologous vaccine as a treatment in different types of cancer. Methods: A total of 31 patients (n=31) with advanced solid tumors and the lack of standard treatments were treated with an immunotherapy protocol consisting of 6 intradermal doses of the vaccine, given the first two doses at day 1 and 2, and the rest every two weeks. All patients signed an informed consent form. Response evaluation was assessed by PET/CT identified as metric (iRECIST) response and in some cases tumor markers where available. Results: Out of 31 patients treated, 2 patients suffered from pancreatic cancer, 2 from sarcoma, 1 from lung cancer, 13 from breast cancer, 2 from ovarian cancer, 1 from prostate cancer, 1 from cholangiocarcinoma, 4 from colorectal cancer, 1 from non-Hodgkin lymphoma, 1 from gastric cancer, 1 from laryngeal and hypopharyngeal cancer, 1 from fallopian tube cancer, 1 from peritoneal cancer. Side effects related to the therapy were rare including light redness in the area of injection and in one case inflammation of the tumor area. 26 patients were evaluated for metric response and 5 for tumor marker response assessment. For tumor marker follow up 9.6 % had a SD of > 3 month and 6.5 % a PD. For metric follow up 12.9 % had a CR, 6.5 % a PR, 25.8 % a SD of > 3 month and 38.7 % a PD. Conclusions: This study have confirmed an anti-tumor response in the majority of patients treated, with none to very low side effects and a good quality of life during the treatment. To obtain more detailed and significant data on the efficacy of this therapy, a further controlled clinical phase study should be performed.
Safety and tolerability of MEDI0562 in combination with durvalumab or tremelimumab in patients with advanced solid tumors.
Authors: Goldman Jonathan Wade , Piha-Paul Sarina Anne , Curti Brendan D. , Pedersen Katrina , Bauer Todd Michael , Groenland Stefanie L. , Carvajal Richard D. , Chhaya Vaishali , Hammond Scott A , Streicher Katie , Townsley Danielle Michelle , Chae Young Kwang , Voortman Jens , Marabelle Aurelien , Powderly John D. 
Published: May 2020

3003 Background: We report safety and tolerability of MEDI0562, a humanized IgG1κ OX40 monoclonal antibody (mAb), in combination with durvalumab (durva; anti-PD-L1 mAb) or tremelimumab (treme; anti-CTLA-4 mAb) in patients (pts) with previously treated advanced solid tumors. Methods: In this phase 1, open-label study (NCT02705482), adult pts received escalating doses of MEDI0562 (2.25, 7.5 or 22.5 mg/kg) every 2 wks (Q2W) in combination with durva (1500 mg/kg) or treme (75 or 225 mg/kg) Q4W, until confirmed disease progression or unacceptable toxicity. Tumor assessments were performed Q8W with immune-related Response Evaluation Criteria in Solid Tumors. Results: In total, 27 and 31 pts received MEDI0562 + durva or treme, across 5 dose combination cohorts (3 + 3 design), with a maximum tolerated dose of 7.5 mg MEDI0652 + 1500 mg durva and maximum administered dose of 10 mg MEDI0562 + 225 mg treme. Median duration of exposure was 12.0 (range 2.0–80.9) and 8.0 (range 2.0–42.0) wks, respectively. Two (22.5 mg MEDI10562 + durva) and 3 (2.25 mg MEDI0652 + 225 mg treme, 22.5 mg MEDI0562 + 75 and 225 mg treme) dose limiting toxicities were observed. For MEDI0562 + durva and MEDI0562 + treme groups respectively, treatment-emergent adverse events (TEAEs) were reported in 96.3% and 100% of pts; most common TEAEs were fatigue (55.6%) and pruritus (45.2%), Gr 3/4 TEAEs occurred in 74.1% and 67.7%; and MEDI0562-related AEs were reported in 20 (74.1%) and 24 (77.4%) pts. Six TEAEs in each group led to MEDI0562 discontinuation (22.2% and 19.4%, respectively), 2 led to death (renal failure [7.5 mg MEDI0562 + durva], multiple organ dysfunction syndrome [22.5 mg MEDI0562 + 225 mg treme]). Three response evaluable pts had PR (11.5% [7.5 and 22.5 mg MEDI0562 + durva, n = 26]). Median overall survival was 17.4 and 11.9 mos for MEDI0562 + durva and MEDI0562 + treme, with stable disease seen in 9 pts from each group, 34.6% vs 29.0%, respectively. Serum exposure of MEDI0562 increased dose proportionally. Post treatment serum antidrug antibody (ADA) was detected in 20 pts from MEDI0562 + durva and MEDI0562 + treme (74.1% and 71.4%, respectively). The impact of ADA on MEDI0562 pharmacokinetics was seen at all doses. Mean percentage of Ki67+CD4+ and Ki67+CD8+ memory T cells increased, while mean percentage of OX40+CD4+ memory T cells decreased following the first dose of MEDI0562 + durva or treme. Conclusions: The safety profile of MEDI0562 in combination with durva or treme was similar between groups. Clinical activity was observed with MEDI0562 + durva in pts with advanced solid tumors. Clinical trial information: NCT02705482 .