tbuckley/cabot-search huggingface dataset:
Safety and efficacy results from a phase I dose-escalation trial of Nintedanib in combination with Pembrolizumab in patients with advanced solid tumors (PEMBIB trial).
Authors: Andreea Varga, Capucine Baldini, Patricia Martin-Romano, Benjamin Besse, David Planchard, Stephane Champiat, ERIC ANGEVIN, Antoine Hollebecque, Rastislav Bahleda, Anas Gazzah, Jean-Pierre Armand, Xavier Paoletti, Christophe Massard, Jean-Charles Soria, Aurelien Marabelle
Journal: Journal of Clinical Oncology (2018)

3080 Background: We aimed to determine the safety and activity of the nintedanib+pembrolizumab combination. Nintedanib is an oral angiokinase inhibitor targeting the vascular endothelial, platelet-derived and fibroblast growth factor receptors as well as RET. Pembrolizumab is a highly selective, humanized monoclonal IgG4–kappa isotype antibody against PD-1 designed to block the negative immune regulatory signaling of the PD-1 receptor expressed by T cells. Methods: PEMBIB is a monocentric phase Ib trial which evaluated escalating doses of nintedanib (Dose level 1 (DL1) = 150 mg BID; DL2 = 200 mg BID) in combination with intravenous flat dose of pembrolizumab at 200 mg every 21 days in patients with advanced solid tumors using the rolling 6 design. A lead-in monotherapy of nintedanib was performed 7 days prior starting pembrolizumab. The primary objective was to establish MTD of this combination based on DLT occurrence during the first 4 weeks (28 days since C1D1) and to determine the recommended phase 2 dose (RP2D). Results: As of November 24, 2016, 13 patients (12 evaluable for DLT) have been enrolled in the escalation part : 2 cervical carcinoma, 1 MSI colorectal cancer, 1 triple negative breast cancer, 2 thymic carcinoma, 1 malignant pleural mesothelioma, 1 peritoneal mesothelioma, 1 gastric adenocarcinoma, 1 renal carcinoma, 1 neuroendocrine tumor, 1 nasopharyngeal cancer. The median age was 54, of these 50% were male, all ECOG 0 (83%) or 1. There were no grade 4-5 toxicities. The adverse events reported for more than 2 patients were alanine & aspartate aminotransferase increase, fatigue, anorexia, diarrhea, nausea, vomiting, hypothyroidism. Three dose-limiting toxicities of liver enzymes elevation were observed in 200 mg BID nintedanib thus recommending 150 mg BID nintedanib for the phase II part. Three patients have developed an objective RECIST partial response (ORR = 25%). Conclusions: Toxicity was consistent with the safety profile of each drug. Additional data for safety and efficacy is being further evaluated in the expansion part of this trial. The efficacy of the combination is currently further explored in 8 expansion cohorts of 30 patients. Clinical trial information: NCT02856425.
Boron neutron capture therapy in non-SCC patients with intractable head and neck malignancies who have no other treatment options.
Authors: Itsuro Kato, Yusei Fujita, Naofumi Yamamoto, Masatoshi Ohmae, Yoshinori Sakurai, Minoru Suzuki, Shin-ichiro Masunaga, Isao Murata, Mitsuhiro Nakazawa, Koji Ono
Journal: Journal of Clinical Oncology (2016)

e17507 Background: Boron neutron capture therapy (BNCT) is a targeted type of radiotherapy that has a number of significant advantages over conventional external beam photon irradiation, especially in that radiation can be selectively delivered to tumor cells. We had, first in the world, treated with BNCT for a patient with recurrent head and neck cancer in 2001. In salivary gland carcinomas and sarcomas at head and neck region, unresectable cases or those with local recurrence after surgery, little efficient treatment modality has been developed. Methods: From December, 2001 to February, 2012, 11 intractable patients with non-squamous cell carcinoma (non-SCC) were treated with BNCT. Histopathologically, there were 7 patients with salivary gland carcinomas and 4 with sarcomas. All of them had received standard therapy and subsequently developed recurrent disease which have no other treatment options. All patients had received intravenously either a combination of two boron containing drugs, sodium borocaptate (BSH) 5g and borono phenylalanine (BPA) 250mg/kg or BPA 500mg/kg alone. Then they were treated with BNCT at the Kyoto University Research Reactor Institute. Results: All patients had advanced disease and 4 of 11(36%) had regional lymph nodes metastasis and distant metastasis, respectively. (1) 10B concentration ratios of tumor/normal tissue (T/N ratio), as determined by 18FBPA-PET imaging were mean 3.0 (2.2-4.0) for sarcomas and 2.8 (2.0-3.7) for salivary gland carcinomas. (2) Regression rates of sarcoma were CR: 2 patients (50%), PR: 2 (50%) patients and those of salivary gland tumor were CR: 4 (57%) and PR: 3 (43%). The overall response rate of both was 100%. (2) The mean survival time was 24.2 months and the 5year OS rates were 50% and 38%, respectively. (3) Survival times following BNCT ranged from 1 to127 months. (4) BNCT improved QOL, PS and survival period. (5) The primary adverse events were brain necrosis, osteomyelitis and transient mucositis and alopecia. Conclusions: Our results indicate that we could make sure that safety and effectiveness of BNCT and BNCT represents a new and promising treatment modality in non-SCC patients for whom there are no other treatment options.
P05.74 Congruence between brain tumor patients and their informal caregivers on patients’ executive functioning
Authors: S D van der Linden, K Gehring, G J M Rutten, M M Sitskoorn
Journal: Neuro-Oncology (2018)

Monitoring of symptoms and quality of life in patients with primary brain tumors is increasingly being supported with information of informal caregivers, but research on patient-proxy agreement is limited. In this study, the level of agreement between patient-report and patient-by proxy-report of executive functioning was evaluated. Data of this study were collected in a larger ongoing prospective study on cognitive rehabilitation in brain tumor patients in the Elisabeth-TweeSteden Hospital Tilburg, The Netherlands (ClinicalTrials.gov NTC03373487). Three months after surgery, patients and their informal caregivers completed the adult version of the Behaviour Rating Inventory of Executive Function (BRIEF-A). This 75-item questionnaire addresses different aspects of executive function. The index-scores, i.e. Behavioral Regulation and Metacognition, and the total scores of patients and proxies were evaluated. Mean scores of patients and proxies were compared using two-tailed paired-sample t-tests. Concordance correlation coefficients (CCCs) were calculated and Bland-Altman plots were evaluated. A total of 43 dyads were included in the study. Patients (51% female) had a mean age of 51.1 (±11.0) years. Twenty-five patients underwent resective surgery for a meningioma and 18 for a low-grade glioma. Mean scores of patients and proxies did not differ significantly (p-values > .05). CCCs of .63, .58 and .63 were found for Behavioral Regulation, Metacognition and the total score respectively, indicating moderate to substantial concordance. Bland-Altman plots demonstrated agreement between patient and proxy ratings, with over 95% of the data points lying between the limits of agreement (Meandiff ± 2SDdiff), for the index and total scores. Preliminary findings suggest that there is congruence between patients and proxies in the evaluation of patients’ executive functioning after brain tumor surgery. Final results from approximately 50 dyads will be presented at the conference. Also, the relation with objective measures of executive functioning will be presented, as well as the potential influence of tumor location and tumor type. This research was supported by the Dutch organization for health research and innovation (ZonMw, project number 842003009).
Food intervention to make therapy with pazopanib more patient-friendly and affordable.
Authors: Floor Lubberman, Hans Gelderblom, Frank Jansman, Angela Colbers, Winette TA van der Graaf, Peter Mulders, David M. Burger, Saskia Luelmo, Jan den Hartigh, Carla M.L. Van Herpen, Nielka P. Van Erp
Journal: Journal of Clinical Oncology (2016)

11040 Background: Pazopanib has been registered for advanced soft tissue sarcoma (STS) and metastatic renal cell carcinoma (mRCC) and is used at a fixed oral dose of 800 mg taken fasted. However, ingesting pazopanib with food is a more patient friendly approach. Moreover, the occurrence of gastro-intestinal adverse events, a well-known side effect of pazopanib, could potentially be reduced when taken with food. Finally, a food intervention resulting in a better absorption and similar exposure to pazopanib, can lead to a reduced dose, which could significantly impact costs. The aim of the study was to establish the bio-equivalent dose of pazopanib taken with a continental breakfast compared to the standard intake of 800mg OD in fasted state. Methods: in this phase I cross-over multi-center study pazopanib pharmacokinetics (PK) were evaluated in STS and mRCC patients treated with 800 mg pazopanib in a fasted state, followed by 600 mg ingested with a continental breakfast based on PK evaluation. After both periods of 14 days, pazopanib plasma exposure was measured. Bioequivalence was assumed when the GMR (fed/fasted) of the AUC0-24h and Cmax and their 90% confidence interval (CI) were within the range of 0.8 and 1.25. Results: 19 patients were enrolled into the study, of whom 16 were eligible for PK analysis. GMR (fed/fasted) AUC0-24h was 1.09 (CI 1.02-1.17) and GMR Cmax was 1.12 (CI 1.04-1.20). 92% of our patients continued to use pazopanib with food. Conclusions: By a simple food intervention a 25% reduced dose of pazopanib results in an exposure, which is bioequivalent to 800 mg OD taken fasted. Most patients in this study choose to continue using pazopanib with food, emphasizing the patient friendliness of this approach for patients with STS and mRCC. Lastly, this approach may contribute to keep oncolytic therapy, such as pazopanib, more affordable and thus probably more available to all patients. Clinical trial information: NCT02138526. n Geometric mean AUC (0-24h) , mg·h/l (95%CI) Cmax , mg/l (95%CI) Tmax , h (range) Fasted (1 dd800 mg) 16 821 (657-1025) 44.8 (36.5-55.2) 3.0 (1.0-5.1) Fed (1dd 600 mg) 16 895 (689-1148) 50.2 (38.8-64.8) 4.0 (3.0-9.1)
Comprehensive genomic profiling of anaplastic thyroid carcinoma.
Authors: Daniel W. Bowles, Jeffrey S. Ross, Laurie M. Gay, Veena Agrawal, Siraj Mahamed Ali, Saad A. Khan
Journal: Journal of Clinical Oncology (2018)

6089 Background: Anaplastic thyroid carcinoma (ATC) is a rare malignancy with a poor prognosis. We queried whether comprehensive genomic profiling (CGP) could uncover biomarkers that could enable targeted and immunotherapies. Methods: CGP was performed on 180 FFPE ATC samples using hybridization-captured, adaptor ligation based libraries to a mean coverage depth of > 500X for up to 315 cancer-related genes. The results were analyzed for all classes of genomic alterations (GA) including short variant (SV) base substitutions and insertions and deletions; select rearrangements; and copy number changes. 408 consecutively sequenced papillary thyroid carcinomas (PTC) were included as a comparison group. Total mutational burden (TMB) was determined on 1.1 megabases of sequenced DNA. MSI status was determined by a proprietary algorithm. Results: There were 88 female (49%) and 92 (51%) male ATC patients with a median age of 64 years (range 25-86 yrs). All ATC cases were submitted as de novo ATC. ATC had significantly higher mean frequency of genomic alterations (GA) per sample and higher frequency of TP53 mutations (Table). In contrast, PTC had significantly higher frequencies of RET and BRAF SV mutations and gene rearrangements in BRAF, RET, ALK and NTRK. TMB levels were similarly low in both groups and no cases featured a MSI-High status. Examples of ATC with responses to targeted therapies will be presented. Conclusions: ATC differs significantly in genomic alterations from classic PTC. Advanced stage PTC and ATC are frequently driven by BRAF GA or oncogenic rearrangements, suggesting ATC might result from dedifferentiation of BRAF mutated PTC. TMB appears to be low for both ATC and PTC. PTC ATC Significance No. Patients 408 180 Median age (years) 59 64 Gender (F/M) 215/193 88/92 GA/tumor 2.75 4.34 Significant genes altered BRAFTERTTP53RET TP53TERTBRAFNRASPIK3CANF1NF2PTEN TP53 GA Frequency 11% 66% P < 0.0001 RET GA Frequency 9% 2% P = 0.002 hTERT Frequency 58% 61% NS BRAF GA Frequency 73% 39% P < 0.0001 BRAF, RET, ALK, or NTRK rearrangements 13% 3% P < 0.0001 Total Mutational Burden ≥10 mut/Mb 2% 3% NS Opportunity for Targeted Therapies High (BRAF, oncogenic fusions) Moderate (BRAF,NF1, NF2, oncogenic fusions)
Safety profile of EP2006 biosimilar filgrastim: A combined analysis of two independent phase III studies.
Authors: Nadia Harbeck, Pedro Gascon, Andriy Krendyukov, Nadja Hoebel, Sreekanth Gattu, Kimberly Blackwell
Journal: Journal of Clinical Oncology (2017)

e21701 Background: The biosimilar filgrastim Zarzio (EP2006) was approved in Europe in 2009 and in 2015 became the first biosimilar approved by the FDA for use in the USA, marketed as Zarxio. Two phase III registration studies were performed to confirm the efficacy and safety of biosimilar filgrastim in women with breast cancer receiving myelotoxic chemotherapy. Methods: Data were combined from the studies to evaluate safety. Study 1 (US registration trial) was a randomized, double-blind comparative study of biosimilar and reference filgrastim (Neupogen, Amgen) in women ≥18 years with breast cancer receiving (neo)adjuvant treatment for 6 consecutive cycles with TAC (docetaxel 75 mg/m 2 , doxorubicin 50 mg/m 2 , and cyclophosphamide 500 mg/m 2 ). Study 2 (EU registration trial) was a single-arm, open-label study of biosimilar filgrastim in women ≥18 years with breast cancer receiving doxorubicin 60 mg/m 2 and docetaxel 75 mg/m 2 for 4 consecutive cycles. In/exclusion criteria and statistical definitions used for both studies were similar. Data of the patients treated with biosimilar filgrastim only were combined for Cycles 1-4. Results: A total of 277 patients (mean±SD age: 51.1±10.8 years) received biosimilar filgrastim (5 μg/kg bw/day sc). Treatment-emergent adverse events (TEAEs) were consistent with the known safety profile of filgrastim. The most frequently reported filgrastim-related TEAEs were musculoskeletal/connective tissue disorders (9.4%), including bone pain (5.8%) (Cycle 1). No neutralizing anti-filgrastim antibodies were detected. Mean±SD duration of severe neutropenia was 1.04±1.51 days in Cycle 1. Mean±SD depth of absolute neutrophil count nadir in Cycle 1 was 0.94±1.40 x 10 9 /L. Conclusions: Safety data for biosimilar filgrastim EP2006 is consistent with reference filgrastim in women with breast cancer undergoing myelotoxic chemotherapy. Clinical trial information: NCT01519700. [Table: see text]
P01.032 Associations of anticoagulant use with outcome in newly diagnosed glioblastoma
Authors: E Le Rhun, E Genbrugge, R Stupp, O L Chinot, L B Nabors, T Cloughesy, D A Reardon, W Wick, T Gorlia, M Weller
Journal: Neuro-Oncology (2018)

To test the hypothesis that, despite bleeding risk, anticoagulants improve outcome in glioblastoma because of reduced incidence of venous thromboembolic events and modulation of angiogenesis, infiltration and invasion. We assessed survival associations of anticoagulant use from baseline up to start of temozolomide chemoradiotherapy (TMZ/RT) (period I) and from there to the start of maintenance TMZ chemotherapy (period II) by pooling data of three randomized clinical trials in newly diagnosed glioblastoma including 1,273 patients. Progression-free survival (PFS) and overall survival (OS) were compared between patients with: anticoagulant use versus no use; therapeutic versus prophylactic versus no use; different durations of anticoagulant use versus no use; anticoagulant use versus use of anti-platelet agents, versus neither nor. Cox regression models were stratified by trial and adjusted for baseline prognostic factors. Anticoagulant use was documented in 75 patients (5.9%) in period I and in 104 patients (10.2%) in period II. Anticoagulant use during period II, but not period I, was associated with inferior OS compared to no use on multivariate analysis (p=0.001, HR=1.52, 95% CI: 1.18–1.95). No decrease in OS became apparent when only patients with prophylactic anticoagulant use were considered. No survival association was established for anti-platelet agent use. Anticoagulant use was not associated with improved OS. Anticoagulants may not exert relevant anti-tumor properties in glioblastoma.
A phase 2 trial of 5-imino-13-deoxydoxorubicin (GPX-150) in metastatic and non-resectable soft tissue sarcomas.
Authors: Brian Andrew Van Tine, Mark Agulnik, Richard D. Olson, Gerald M. Walsh, Arthur Klausner, Mohammed M. Milhem
Journal: Journal of Clinical Oncology (2016)

11019 Background: 5-imino-13-deoxydoxorubicin (GPX-150) is a doxorubicin (dox) analog that has been modified to retain the ability to inhibit topoisomerase 2a while simultaneously lacking the inhibition of topoisomerase 2b, the ability to form cardiotoxic metabolites, or the ability to recycle through a redox mechanism. In the phase 1 trial, GPX-150 showed no irreversible cardiotoxicity. Preclinical studies and the Phase 1 clinical trial suggested anticancer activity in soft tissue sarcoma (STS). Methods: We performed a Phase 2 efficacy and safety study in 22 patients enrolled with locally advanced and/or metastatic intermediate or high grade soft tissue sarcoma (STS). The open-label single arm study of GPX-150 was performed in the front line setting. Patients who met all entry criteria received GPX-150 at a starting dose of 265 mg/m2 along with pegfilgrastim every 21 days for up to 16 cycles or until death, disease progression, or unacceptable toxicity. Using RECIST 1.1, response evaluations were performed every 6 weeks for the first 24 weeks, then every 9 weeks for the remainder of the trial. Safety and toxicity data were obtained. Results: Of 21 evaluable patients for efficacy, there was a 38% Clinical Benefit Rate at 16 weeks. One patient had a partial response and 8 patients had stable disease (SD) for at least 6 cycles. Two patients had grade 3-4 neutropenia (8%); 1 patient had grade 3 febrile neutropenia (4%); 3 patients (14%) had grade 3 anemia. All other toxicities including mucositis, nausea, vomiting, alopecia and fatigue were less than grade 3. A reversible, asymptomatic left ventricular ejection fraction fall to below 50% (MUGA) occurred in 3 patients. Conclusions: Anticancer activity was demonstrated in patients with STS. There was no irreversible cardiotoxicity. GPX-150 was well tolerated. Other than hematological toxicity, no grade 3 or 4 toxicities occurred. Clinical trial information: NCT02267083.
Effect of Aspirin on All-Cause Mortality in the Healthy Elderly
Authors: John J. McNeil, Mark R. Nelson, Robyn L. Woods, Jessica E. Lockery, Rory Wolfe, Christopher M. Reid, Brenda Kirpach, Raj C. Shah, Diane G. Ives, Elsdon Storey, Joanne Ryan, Andrew M. Tonkin, Anne B. Newman, Jeff D. Williamson, Karen L. Margolis, Michael E. Ernst, Walter P. Abhayaratna, Nigel Stocks, Sharyn M. Fitzgerald, Suzanne G. Orchard, Ruth E. Trevaks, Lawrence J. Beilin, Geoffrey A. Donnan, Peter Gibbs, Colin I. Johnston, Barbara Radziszewska, Richard Grimm, Anne M. Murray
Journal: New England Journal of Medicine (2018)

In the primary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, now published in the Journal, we report that the daily use of aspirin did not provide a benefit with regard to the primary end point of disability-free survival among older adults. A numerically higher rate of the secondary end point of death from any cause was observed with aspirin than with placebo.
Expression of estrogen receptor variants in ER+ basal-type breast cancers that respond to therapy like ER- breast cancers.
Authors: Pat W. Whitworth, Paul Baron, Peter D. Beitsch, Erin Yoder, Tina Treece, M. William Audeh, Winand N.M. Dinjens, Rene Bernards, Floris Groenendijk
Journal: Journal of Clinical Oncology (2018)

e24289 Background: Gene expression analysis using the 80-gene signature (80-GS) classifies breast cancers as luminal-, basal- or HER2-type based on intact signaling within the corresponding molecular pathways. We previously showed that a subset of ER+HER2- tumors are reclassified to molecular basal-type by the 80-GS. Here we investigated whether molecular reclassification was associated with expression of dominant negative ER variants, and comparatively evaluated response to therapy and 3-year outcome. Methods: The 80-GS reclassified 90 (18%) ER IHC+ tumors from the neoadjuvant NBRST study (NCT01479101) to basal-type. ER variant analysis was run for 84 available ER+/basal and 48 ER+/luminal-B control patients (Pts). Expression of total ER and ER variants mRNA (ER∆3, ER∆7 and ERα-36) were determined by real-time qPCR. Kaplan Meier survival analysis included HER2- NBRST Pts with follow-up information. Results: Total ER mRNA was significantly lower for ER+/basal tumors compared to ER+/luminal tumors (P < 0.001). The ER∆7 splice variant was the highest expressed ER variant in both subgroups. The relative expression of ER∆7/total ER was significantly higher in ER+/basal tumors compared to ER+/luminal tumors (P < 0.001). From the larger cohort of NBRST Pts, the ER+/basal Pts had similar pCR rates following neoadjuvant treatment as ER-/basal Pts (35% vs 38%), and much higher than ER+/luminal-A or B Pts (2% and 6%). Furthermore, 3-year distant metastasis-free interval (DMFI) was 66% for ER+/basal Pts, comparable to ER-/basal Pts (75%), and much lower than 96% and 89% for luminal-A and B Pts respectively. Conclusions: Significantly lower total ER mRNA expression and increased relative expression of the ER∆7 splice variant provide a rationale why ER+/basal-type breast cancers are transcriptionally ER-negative. Identification of this substantial subset of patients is clinically relevant because of the higher pCR rate to neoadjuvant chemotherapy and correlation with clinical outcome. Clinical trial information: NCT01479101.IHC/80-GS Subtype pCR DMFI at 3yrs (95% CI) ER-/Basal (N = 224) 38% 75% (68-83%) ER+/Basal (N = 69) 35% 66% (52-83%) Luminal-A (n = 129) 2% 96% (91-100%) Luminal-B (N = 236) 6% 89% (84-94%)