bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrated data review of the first-in-human dose (FHD) study evaluating safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor, LY2157299 monohydrate (LY).
Authors: Rodon Jordi , Carducci Michael Anthony , Sepúlveda Juan Manuel , Azaro Analia , Calvo Emiliano , Seoane Joan , Brana Irene , Sicart Elisabet , Gueorguieva Ivelina , Cleverly Ann , Pillay Sada , Desaiah Durisala , Lahn Michael M. F. , Paz-Ares Luis , Holdhoff Matthias , Blakeley Jaishri O'Neill , Baselga José 
Published: March 2020

2016 Background: Activated TGF-ß signaling has been associated with poor survival in several tumors, including glioma (GM). Hence, we investigated the safety, PK and antitumor responses of the novel TGF-ß inhibitor LY in cancer patients, mainly in GM. Methods: There were 3 study parts: Part A: dose escalation of LY monotherapy in patients with solid tumor (cohorts 1 and 2, continuous dosing) and with GM (cohorts 3 to 5, intermittent dosing 14 days on/14 days off); Part B: intermittent LY dosing in combination with lomustine; Part C: monotherapy of 300 mg/day in solid tumors after completing a relative bioavailability study. Safety, antitumor activity, PK and PD were assessed as previously described (Calvo-Aller, et al. JCO 2008;26:abstract #14554; Rodon, et al. JCO 2011;29:abstract #3011; Azaro, et al. JCO 2012;30:abstract #2042). Results: 79 patients participated in this study (Part A, n = 39, 7 solid tumor, 32 GM; Part B, n = 26, all GM; Part C, n = 14 solid tumor, 9 GM, 2 hepatic cell carcinoma [HCC], 2 gastrointestinal [GI] and 1 melanoma). The integrated safety and efficacy evaluation confirms that LY has a manageable toxicity profile with antitumor activity. For GM patients the median progression-free survival (PFS) in months (range) was: 2.5 (0.0 to 36.9) in Part A; 2.5 (0.0 to 20.5) in Part B; 1.9 (0.0 to 6.4) in Part C. PFS duration in months were (range): 2.1-3.8 for HCC; 1.2-3.9 for GI and 2.2 for melanoma patient. Responders were observed in primary GM (Part A: 3/16; Part B: 2/20) and secondary GM (Part A: 3/14; Part B: 4/6). As of January 2013, 3 GM patients are still on treatment for 54, 36, and 31 months. P450-inducing medications including proton pump inhibitors or enzyme-inducing anti-epileptic drugs did not influence the PK parameters. Approximately, 90 biomarkers have been assayed and the results will be presented during the meeting. Conclusions: Because of the manageable toxicity profile of LY, the 300 mg/day dose administered as an intermittent dosing has been advanced into phase II investigation, either as a monotherapy or in combination with approved chemotherapies. Clinical trial information: NCT01682187.
BTTC08-01: A phase II study of bevacizumab and erlotinib after radiation therapy and temozolomide in patients with newly diagnosed glioblastoma (GBM) without MGMT promoter methylation.
Authors: Raizer Jeffrey J. , Giglio Pierre , Hu Jethro Lisien , Groves Morris D. , Merrell Ryan , Conrad Charles A. , Phuphanich Surasak , Puduvalli Vinay K. , Loghin Monica Elena , Paleologos Nina , Yung W. K. Alfred , Vaillant Brian D. , Rudnick Jeremy David , Chamberlain Marc C. , Vick Nicholas , Grimm Sean Aaron , Tremont-Lukats Ivo , De Groot John Frederick , Aldape Kenneth D. , Gilbert Mark R. 
Published: March 2020

2019^ Background: Patients (pts) with GBM with unmethylated MGMT have a worse prognosis than those with methylated MGMT. Novel approaches for this poor risk group are warranted. The Brain Tumor Trials Collaborative (BTTC) performed a phase II trial evaluating standard chemoradiation followed by bevacizumab and erlotinib in patients with MGMT unmethylated GBM. EGFR and VEGFR are upregulated during radiation suggesting that this combination could be more effective than post-radiation adjuvant temozolomide (TMZ). Methods: After informed consent, adult patients with supratentorial GBM, KPS ≥ 70 and > 1 cm2 tumor block for MGMT promoter analysis were screened. Only tumors with confirmed unmethylated MGMT promoter were enrolled. All patients received RT + TMZ and then approximately 4 weeks after RT they received bevacizumab 10 mg/kg every 2 weeks and erlotinib 150 mg/day, continuously. One cycle was 4 weeks; evaluation by MRI was every 2 cycles. Treatment continued until disease progression or intolerable adverse events. Results: 115 patients were screened; 48 were enrolled (2 unevaluable: 1 for an infratentoral GBM and 1 withdrew after 7 days of treatment) with 29 men, 17 women. Median age was 56 yrs (29-75); median KPS was 90 (70-90). The median number of cycles was 8 (2-38) with 4 patients remaining on trial at the time of analysis. Objective responses: 4 CR, 12 PR and 30 SD. Median PFS is 7.3 months (95% CI (6.4, 11)) and median OS 14.2 months (95% CI (10.7, not reached)). There were no unexpected toxicities; grade 3/4 rate < 5%. Conclusions: Adjuvant bevacizumab and erlotinib in GBM with unmethylated MGMT is well tolerated. Preliminary efficacy data is comparable with outcomes in similar unmethylated MGMT patient populations from the EORTC/NCIC and RTOG 0525 studies. Tissue correlation is being performed. Clinical trial information: NCT00720356.
Use of DNA copy number analysis of grade 2-4 gliomas to reveal differences in molecular ontogeny associated with IDH mutation status.
Authors: Sato Mariko , Aldape Kenneth D. , Mason Clinton C , Diefes Kristin , Heathcock Lindsey , Abegglen Lisa , Schiffman Joshua David , Colman Howard 
Published: March 2020

2026 Background: The genetic alterations of glioma have been studied extensively. IDH1 mutation is associated with younger age and better survival. However, differences in molecular ontogeny within glioma related to IDH1 mutation remain unknown. Here we describe a detailed analysis of copy number alterations (CNA) between IDH1mut vs IDH1wt gliomas of grade 2-3 and 4. Methods: CNA were detected by molecular inversion probes (Affymetrix) and analyzed with Nexus Copy Number Software (BioDiscovery). DNA was extracted from 94 patient FFPE samples including grade 2-3: IDH1wt (n = 17) and IDH1mut (n = 28), and grade IV: IDH1wt ( n = 25) and IDH1mut(n = 24). Chromothripsis was detected using a stringent criteria of at least ten switches of CNA in individual chromosomes. Results: We validated prior findings that IDH1wt GBM have higher frequency of Chr7 amplification (including EGFR) and loss of Chr10 (including PTEN). Other CNA across all grades were: gain of 19q12 and loss of 14q11 in IDH1wt, and gain of 11q21, 10p11, 8q21 and loss of 11p15, 19q13 in IDH1mut. Within grade 2-3 samples, few CNA were associated with mutation status: 2-3wt demonstrated higher frequencies of gain of 7q and loss of 10q, 14q11, and 22q13, while 2-3mut demonstrated higher frequencies of 11q21 gain and 19q13 loss. Grade 4 tumors demonstrated more CNA that differed by mutation status, with 4wt tumors demonstrating gain of 7 and loss of 10 and 14q11, while 4mut demonstrated gains of 8q, 10p, 12p13, 1q23, and loss of 11p15, 3p, 19q13, among others. Comparison of grade 2-3mut vs grade 4mut tumors demonstrated larger number of CNA in the grade 4mut tumors including gain of 1p, 14q, 13q33, 9p, 8q and loss of 22q, 11p15, 10q, and 3p, among others. A significantly higher incidence of chromothripsis events was observed in grade 4mut compared to grade 4wt (p = 0.0374). Conclusions: CNA analysis showed significant differences in molecular ontogeny between IDH1wt and IDH1mut, some of which may further elucidate pathogenesis. Significant CNA increases and increased chromthripsis in grade 4mut support malignant transformation of low grade gliomas through accumulation of genomic instability and genomic catastrophe.
Prognostic utility of neuraxis imaging in leptomeningeal metastasis (LM): A retrospective case series.
Authors: Chamberlain Marc C. 
Published: March 2020

2037 Background: Correlate imaging of the central nervous system that includes both brain and spine MRI and radio-isotope cerebrospinal fluid [CSF] flow studies with survival in a retrospective case series of patients with LM. Methods: 240 adult patients with LM (125 non-brain solid tumor patients with positive CSF cytology; 40 non-brain solid tumor patients with negative CSF cytology and MRI consistent with LM; 50 lymphoma and 25 leukemia patients with positive CSF flow cytometry), all considered appropriate for LM-directed treatment, underwent prior to treatment brain and entire spine MRI and radio-isotope CSF flow studies. Results: Median overall survival was significantly shortened in patients with large volume MRI defined disease (defined as measurable tumor > 5 x 10 mm in orthogonal diameters) and in patients with non-corrected CSF flow obstruction irrespective of primary tumor histology. Additionally, cause of death differed wherein patients with large volume of disease or uncorrected obstructed CSF flow more often died of progressive LM disease whereas patients with normal or small volume disease and patients with normal or re-established CSF flow more often died of progressive systemic disease. Conclusions: Neuraxis imaging utilizing brain and spine MRI as well as radio-isotope CSF flow studies appears to have prognostic significance and may be predictive of median overall survival in this large cohort of patients with LM all of whom were considered for treatment with LM.
Factor Xa: PAR-1 growth loop is blocked by low-molecular weight heparins—A new perioperative and adjuvant concept in glioblastoma.
Authors: Kuhn Susanne Antje , Kratzsch Tobias , Gruenwald Viktor , Haberl Hannes 
Published: March 2020

2038 Background: Glioblastoma patients suffer from thromboembolism, aggravating the disease. Recently, increased activity was shown for coagulation factors II, VIII, IX, X, XI, and XII in patient peripheral blood. In vitro, the high potential of FXa-PAR1-loop as growth factor system and significant effects of its blockade were proven. Methods: Patient samples (n=108) were analyzed for FXa and PAR-1. In immunodeficient mice, glioblastoma xenografts were established and treated with low-molecular weight heparins (LMWH) (30mg/kg SC daily for 3 wks). Phosphate buffered saline served as control. Tumor growth rates, final tumor size, tumor proliferation (Ki67), and tumor vascularization (CD31) were determined. Results: Human glioblastomas overexpressed FXa and PAR-1 in the compact tumor center (FXa: p<.001; PAR-1: p<.001) and in the invasion zone (FXa: p=.006; PAR-1: p=.005). Neoangiogenic endothelial cells disproportionately high expressed FXa and PAR-1 with rising intensity in the invasion zone (FXa: p<.001; PAR-1: p<.001), and the compact tumor mass. (FXa: p<.001; PAR-1: p<.001). Growth curves of LMWH-treated tumors slowed (p<.001). Final tumor size was reduced (s.c.: p<.001; i.c.: p<.05). Tumor cell proliferation was massively inhibited in situ (tinzaparin: p<.001; enoxaparin: p<.001) as was the number of CD31 positive endothelial cells ((tinzaparin: p<.001; enoxaparin: p<.001) and the tumor vascularization (p<.001 each). Conclusions: Glioblastoma patients display abnorm activation of coagulation factors in peripheral blood and show high levels of FXa and PAR-1 in the tumor center, invasion zone and angiogenic endothelia. LMWH caused tumor growth retardation and size reduction with blockade of proliferation and vascularization. FXa inhibition should be considered as continuous thrombosis prophylaxis and adjuvant glioblastoma treatment.
Characterization of candidate tissue and blood biomarkers in a rare cohort of myxopapillary ependymoma patients.
Authors: Ilhan-Mutlu Aysegul , Berghoff Anna Sophie , Wrba Friedrich , Marosi Christine , Wagner Ludwig , Zielinski Christoph , Preusser Matthias 
Published: March 2020

2040 Background: Myxopapillary ependymoma (MPE) is a very rare tumor of the distal spinal cord. Despite benign histopathology, local recurrences occur in approximately 30% of patients and distant metastases have been described in few cases. We investigated candidate tissue and blood biomarkers in a rare MPE series. Methods: Formalin fixed paraffin embedded (FFPE) tumour tissues from 21 MPE patients were immunohistochemically investigated for expression of isocitrate dehydrogenase 1 R132H (IDH-R132H), Secretagogin, glial fibrillary acidic protein (GFAP), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), progesterone receptor (PR), estrogen receptor (ER), Ki-67, arg, plateled derived growth factor a (PDGFRa) and b (PDGFRb), pc-kit and pc-abl. EGFR gene was evaluated using exon-sequencing. In addition, we analyzed circulating plasma-GFAP using ELISA in 3 patients with completely resected MPE, 1 patient with locally advanced MPE, 2 patients with pleuropulmonary metastases of MPE and 12 control subjects. Results: Secretagogin and GFAP were expressed in all tissue samples. arg, PDGFRa, PDGFRb, pc-kit and pc-abl were positive in 15, 1, 2, 3 and 2 patients, respectively. The Ki-67 index ranged from 1% to 12.8% (median=7.1%). We detected no expression of EGFR, IDH-R132H, HER2, PR or ER. One patient showed a silent mutation in exon 21 of the EGFR gene (c.2508C>T). We found very high concentrations of plasma-GFAP in two MPE patients with pleuropulmonary metastases, while all other MPE patients were negative. Conclusions: Our data indicate that (i) targeted tyrosine kinase inhibitors may be rational for the therapy of selected MPE patients and that (ii) circulating GFAP could be useful as circulating marker for the early detection or follow-up of distant metastases in MPE patients.
Biomarker analysis of glioblastoma and potential implications for therapy.
Authors: Xiu Joanne , Feldman-Moreno Rebecca Anne , Arguello David , Gatalica Zoran , Ghazalpour Anatole , Bender Ryan P. , Castro Michael , Reddy Sandeep K. , Basu Gargi Dan , Paul Les 
Published: March 2020

2041 Background: Glioblastoma multiform (GBM), the most aggressive CNS cancer, has limited effective therapeutic options, with underlying molecular heterogeneity contributing to the differences in treatment response. Our study was designed to interrogate biomarkers from a large cohort of GBM patients to seek therapeutic implications. Methods: Data was analyzed from 570 high grade astrocytoma patients (vast majority GBM) who received tumor profiling at Caris Life Sciences from 2009 to 13. Test methodologies included IHC, FISH, CISH, Sanger SEQ, MGMT promoter methylation and NextGen SEQ (Illumina TruSeq). Results: In our patient cohort, 59% had MGMT methylation and 70% had negative MGMT IHC, predicting potential response to temozolomide. Protein expression for ERCC1, TOPO1, and TS was 53% negative, 49% positive, and 37% negative, indicating potential benefit from cisplatin, irinotecan and fluorouracil, respectively. Drug pumps PGP and MRP1, were positive by IHC in 10% and 67% of patients, suggesting possible resistance to etoposide, vinca alkaloids and methotrexate. For targeted therapies, c-Kit IHC was positive in 7% patients, mutated in 6% and PDGFRA IHC was positive in 27%, indicating potential benefit from imatinib and other TKI’s. RAS/RAF and PIK3CA/mTOR pathway activation was also noted with BRAF, KRAS, PIK3CA mutations and PTEN loss, observed in 8%, 3%, 7% and 10% of cases, respectively. TS negativity was seen in 91% of MGMT methylated patients and in 37% of MGMT unmethylated patients (p = 0.025, student’s t-test), revealing a possible novel combination therapy of fluoropyrimidines with temozolomide for a select cohort. Similarly, biomarker profiles of molecular subgroups defined by EGFR amplification (44% in our cohort) and IDH1, p53 mutations will be analyzed for therapeutic implications. Conclusions: By profiling tumor biomarkers from a large cohort of GBM patients using validated assays in a single facility, we demonstrate the vast molecular heterogeneity of GBM and highlight the importance of individualized therapy based on a patient’s unique tumor profile. Incorporating a comprehensive biomarker analysis into clinical management of this aggressive cancer allows for an informed selection of more effective therapies.
Phase I/II trial of vorinostat combined with temozolomide (TMZ) and radiation therapy (RT) for newly diagnosed glioblastoma (GBM) (N0874-ABTC0902, Alliance): Final results of the phase I trial.
Authors: Galanis Evanthia , Sarkaria Jann Nagina , Anderson S. Keith , Wu Wenting , Jaeckle Kurt A. , Giannini Caterina , Buckner Jan C. , Wen Patrick Y. ,   Alliance for Clinical Trials in Oncology
Published: March 2020

2046 Background: Vorinostat (VOR) is a histone deacetylase inhibitor that represents a rational targeted agent in GBM treatment. Given its single-agent activity in recurrent disease (Galanis,et al, 2009) and radiosensitizing properties, this phase I/II trial was designed to test the addition of VOR to standard chemoradiation in newly diagnosed GBM patients (pts): the phase I portion of the trial is the focus of this report. Methods: A standard cohorts of three design was used to assess the safety of VOR in combination with RT and concomitant TMZ and establish the phase II dose of the combination. VOR was given orally days 1 - 5 every wk beginning with the first dose of RT (total dose 60 Gy) and (75mg/m²/day). Following a 4 - 6 week rest, pts received up to 12 cycles of standard adjuvant TMZ in combination with VOR on days 1-7 and 15 – 21 of each cycle; dose was based on NABTT trial 04-03 (Lee, et al, 2012). Results: The phase I component is complete with 15 pts, 12 pts at dose level 0 (VOR 300 mg/day days 1 - 5, weekly x 6 wks), and 3 pts at dose level 1 (VOR 400 mg/day, days 1 – 5 weekly x 6 wks) in combination with RT/TMZ. Dose limiting toxicity (DLT) in dose level 1 included grade 3 fatigue in 2 pts, grade 3 wound dehiscence in 1 pt, and grade 4 neutropenia and thrombocytopenia in 1 pt. In dose level 0, 1/6 pts had DLT (gr 3 dyspnea). An MTD expansion cohort of 6 additional patients was added to dose level 0; one patient experienced grade 4 thrombocytopenia and grade 3 fatigue, and 1 patient experienced grade 3 febrile neutropenia. In the 12 pts treated in the phase II dose, most common toxicities were hematologic, including lymphopenia (gr 3/4 in 66.7%), thrombocytopenia (gr 3 in 16.7%, gr 4 in 16.7%) and neutropenia (gr 3 in 16.7%, gr 4 in 8.3%). Grade 3 fatigue was observed in 8.3% of the pts. Conclusions: MTD for VOR in combination with TMZ/RT in newly diagnosed GBM patients is 300 mg/d, days 1 - 5 weekly during RT. Toxicity was primarily hematologic. This dose was used in the recently completed phase II trial of the combination (110 pts). RNA expression profiling in patient samples is in process to assess vorinostat responsive signatures observed in preclinical models. Clinical trial information: NCT00731731.
Marrow-ablative chemotherapy followed by tandem autologous hematopoietic cell transplantation (AuHCT) in pediatric patients with malignant brain tumors.
Authors: Guerra Jhon , Dhall Girish , Marachelian Araz , Castillo Esmeralda , Malvar Jemily , Sposto Richard , Wong Kenneth , Finlay Jonathan L. 
Published: March 2020

2049 Background: In an effort to both improve cure rates and quality of survival in young children with malignant brain tumors, irradiation-avoiding or at least minimizing marrow-ablative chemotherapy with AuHCT has been incorporated in both up-front as well as recurrent therapies. To decrease the toxicity of single cycle marrow-ablative chemotherapy regimens, and possibly enhance cure through overall dose intensification, use of fractionated multiple (tandem) cycles of marrow-ablative chemotherapy with AuHCT has been explored. Methods: In this retrospective analysis, we investigated the outcome of children with malignant brain tumors treated with marrow-ablative chemotherapy and tandem AuHCT at Children’s Hospital Los Angeles between June 1999 and July 2012. Results: Forty-four children (24 males) with a median age of 7.1 years (range 0.6- 19.0 years) with malignant brain tumors were studied. Twenty-one had medulloblastomas/primitive neuro-ectodermal tumors, 8 atypical teratoid/rhabdoid tumors, 5 high-grade gliomas, 4 malignant germ cell tumors, 3 ependymomas and 3 choroid plexus carcinomas. Twenty-nine patients receive 3 and 15 received 2 tandem transplants, respectively. Twenty-seven patients were newly-diagnosed and 17 recurrent disease. Thirty-one patients received irradiation at some time. The 5-year post-transplant progression-free (PFS) and overall survivals (OS) for all patients were 46.3±8.2% and 51.7±8.5% respectively. The PFS and OS for newly-diagnosed patients were 68.9 ± 9.9% and 73.5±9.3% respectively, compared with those transplanted at relapse 11.8±9.8 (p <0.001) and 15.1±12.3% (p = 0.0231) respectively. The 5-year post-transplant PFS and OS in unirradiated patients was 74.0±13.0% and 74.0±13.0% versus33.2±9.8% and 40.2+/-10.6% in irradiated patients (p = 0.11 and p = 0.239 respectively). One patient (2.3%) died of transplant-related toxicity. Conclusions: Marrow-ablative chemotherapy with tandem AuHCT is feasible and safe in children with malignant brain tumors with encouraging irradiation-free survival in newly-diagnosed children.
Phase II study of PX-866 in recurrent glioblastoma.
Authors: Pitz Marshall W. , Eisenhauer Elizabeth A. , MacNeil Mary Valeria , Thiessen Brian , Macdonald David R. , Easaw Jacob C. , Eisenstat David Daniel , Kakumanu Ankineedu Saranya , Squire Jeremy , Tsao Ming Sound , Kamel-Reid Suzanne , Tassignon Aurelie , Hausman Diana Felice , Mason Warren P. 
Published: March 2020

2053 Background: Glioblastoma (GBM) is the most aggressive malignancy of the central nervous system. The majority have genetic changes that increase the activity of the phosphatidylinositol-3-OH kinase (PI3K) signal transduction pathway, critical for cell motility, proliferation, and survival. We present the results of PX-866, an oral PI3K inhibitor, in patients (pts) with recurrent GBM. Methods: A multinomial design of response and early progression (< 8 weeks on study) was used. In stage 1 (15 pts), 0 responses and ≥ 10 early progressions would stop accrual; after full accrual, ≥ 4 responses OR ≤ 13 early progressions was prespecified as of interest. Pts with histologically confirmed GBM, at first recurrence after chemoradiation and adjuvant temozolomide were given PX-866 8 mg daily on this single-arm phase II study. MRI and clinical exam were done every cycle (8 weeks). Tumour tissue was collected for analysis of potential markers of PI3K inhibitory activity (PTEN, EGFRviii, PIK3CA mutations). Results: A total of 33 pts were enrolled, eligible and evaluable. Median age was 56 (range 35-78), 12 were female; 29 had performance status (PS) 0-1 and 4 had PS 2. Median time from initial diagnosis to enrolment was 308 days (range 141-1256). Median number of cycles was 1 (range 1-7). Thirty-two pts have discontinued therapy, 26 due to disease/symptomatic progression and 6 due to toxicity (5 LFT elevation and 1 allergic reaction). Other adverse effects (AE): fatigue (16 pts/2 grade 3), diarrhea (11 pts/5 grade 3), nausea (19 pts/1 grade 3), vomiting (11 pts/1 grade 3) and lymphopenia (29 pts/7 grade 3/4). Five pts had related serious AEs (1 LFTs, 1 GI and 3 venous thromboembolism) All pts were evaluable for response; 25 had a best response of progression, 1 had partial response (overall response rate 3%) and seven (21%) had stable disease (SD, median 7.3 months; range 3.1-13.6). Six month PFS was 17%. In preliminary analyses, no statistical association was found between SD and PTEN or EGFRviii status (results pending in 16 pts). Conclusions: PX-866 was relatively well tolerated. Overall response rate was low, and the study did not meet its primary endpoint; however, 21% of pts obtained durable stable disease. Further correlative work is required to identify the predictor of this effect. Clinical trial information: NCT01259869.