tbuckley/cabot-search huggingface dataset:
Preliminary safety, pharmacokinetics, and efficacy results from an open-label, multicenter, Phase I/II study of avapritinib in Chinese patients with unresectable or metastatic gastrointestinal stromal tumors (GIST).
Authors: Jian Li, Jifang Gong, Xicheng Wang, Jie Li, Yan Li, Changsong QI, Lin Shen, Wenxiao Ren, Wanqi Zhao, Yedong Wang, Jin Hu, Chunli Ren, Wenjie Song, Jianxin Yang
Journal: Journal of Clinical Oncology (2020)

e23526 Background: More than 85% of GIST patients (pts) have tumors associated with KIT or PDGFRA mutations. Avapritinib is a potent, selective, small-molecule inhibitor that targets KIT/PDGFRA activation loop mutants. Recently FDA approved avapritinib for pts with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including D842V mutations based on a robust ORR (84%) in the NAVIGATOR study. This abstract reports preliminary results from the dose escalation part of the bridging study in Chinese pts with advanced GIST. Methods: Adult pts with unresectable or metastatic GIST that progressed after imatinib and ≥ 1 other tyrosine kinase inhibitor, or could not tolerate the standard treatment or had PDFGRA D842V mutation were enrolled and treated with avapritinib once daily (QD) in continuous 28-day cycles following a modified 3+3 dose escalation design. Primary objectives included determination of Recommended Phase II dose (RP2D) and assessment of safety. PK parameters and response per mRECIST v1.1 for GIST were also assessed. Results: As of 25 Dec 2019, 12 pts were treated with avapritinib QD at a starting dose of 200 mg or 300 mg (6 per group). No dose-limiting toxicities were observed. Most treatment-emergent adverse events (TEAEs) were Grade (G) 1-2, most commonly blood creatine phosphokinase increased (n = 9) and blood bilirubin increased (n = 8). There were no G4-5 TEAEs. The most frequent G3 treatment-related TEAE was anaemia (n = 2). Serious adverse events were observed in 1 pt (renal hydrocele) in 200 mg group and 2 pts (abdominal distension and anaemia) in 300 mg group, all were G3 and considered unrelated to avapritinib. No AEs leading to drug discontinuation occurred. Avapritinib was rapidly absorbed (median T max 2.0-4.0 h) and the exposure increased proportionally with doses at the steady state. The mean half-life of avapritinib ranged 42.2-44.4 h, supporting QD dosing. Of the 3 pts with PDGFRA D842V mutation (all in the 300 mg group), 2 pts achieved PR, and 1 had SD, as assessed by investigators at the first tumor assessment. Conclusions: Avapritinib appears generally tolerable at 200 mg and 300 mg QD and shows clinical activity in Chinese pts with PDGFRA D842V mutation. Based on the safety profile in Chinese pts and dose selection results in NAVIGATOR study, 300 mg QD was determined to be the RP2D for Chinese pts. The preliminary safety, PK, and efficacy data support further investigation of avapritinib in Chinese pts with GIST. Clinical trial information: NCT04254939 .
Post-remission clonal hematopoiesis; Practical implications for measurable residual disease assessment in acute myeloid leukemia (AML).
Authors: Sanam Loghavi, Tomoyuki Tanaka, Ken Furudate, Sa A Wang, Koichi Takahashi
Journal: Journal of Clinical Oncology (2020)

7529 Background: Clonal Hematopoiesis may persist following complete remission (CR) in patients with acute myeloid leukemia (AML) but does not necessarily indicate residual AML and may represent persistence of pre-leukemic stem cells. Post-remission CH identified by NGS has not been systemically studied in parallel with measurable residual disease (MRD) detection by flow cytometric immunophenotyping (FCI). Methods: We studied bone marrow sample from AML patients at baseline and CR by targeted deep NGS of 295 genes (median 403x depth) and compared the results to FCI. Measurable residual disease (MRD) detection by FCI was performed by comparing the phenotype at CR to baseline and by detection of leukemia associated immunophenotype (LAIP) and derivation from normal (DFN) (sensitivity: 0.1%). Post-CR CH was defined as presence of mutations originally detected in AML with variant allele frequency &gt; 2.5%. FCI results were categorized into 4 groups: a) AML MRD negative by LAIP or DFN b) AML MRD+ (similar to baseline) c) AML MRD+ (different from baseline), d) Negative for AML MRD, but aberrant phenotype suggestive of pre-leukemic cells. We correlated FCI and NGS results. Results: 101 patients were included in the study. 45 (45%) had persistent post-CR clonal hematopoiesis; 23 (51%) had phenotypic alterations detected by FCI including AML MRD+ in 18 (40%) and pre-leukemic cells in 5 (10%). Among patient with no detectable mutations by NGS (n = 56; 55%), 14 (25%) had FCI aberrancies including AML MRD+ in 4 (7%) and pre-leukemic cells in 10 (18%). CH was significantly more common in samples with residual phenotypic aberrancies detected by FCI (p = 0.004). There was no significant correlation between FCI group d and persistent CH (p = 0.4). Persistent ASXL1 (p = 0.024, OR = 7.2 ) and RUNX1 (p = 0.016; OR = 17.3) mutations were significantly associated with FCI abnormalities. The correlation coefficient between FCI abnormalities and RUNX1 mutations inferred from a Bayesian network structure was 0.66. Conclusions: NGS and FCI are complementary in evaluating post treatment disease status in AML. Post CR-CH is associated with phenotypic abnormalities that either represent residual AML or pre-leukemic cells. The latter may not have the same prognostic implications as AML MRD; however, the association with outcome needs to be elucidated. Single cell DNA sequencing technologies may be helpful in more accurately deciphering the association of individual gene mutations and their contribution to phenotypic aberrations.
Efficacy and safety of liposomal mitoxantrone (Lipo-MIT) in advanced breast cancer (ABC): A randomized, open label, active-controlled, single-center, phase II clinical trial.
Authors: Leiping Wang, Yannan Zhao, Ting Li, Jun Cao, Yiqun Du, Zhonghua Tao, Wenxia Peng, Biyun Wang, Jian Zhang, Zhonghua Wang, Xiulin Huan, Jing Dou, Chunyan Hao, Xiaojing Li, Xiaodong Wang, Zhibin Meng, Yanan Lv, Cuixia Gao, Xi-Chun Hu
Journal: Journal of Clinical Oncology (2020)

1093 Background: Anthracyclines are associated with cardiotoxicity and myelosuppression in breast cancer (BC) patients. A new drug delivery system, liposomal preparation has shown higher anti-cancer effect and lower toxicity due to modified drug release and particle shape. This trial aimed to evaluate the efficacy and safety of Lipo-MIT in ABC. Methods: This is a randomized, open label, active-controlled, single-center, phase II clinical trial. Eligible patients were randomized in a ratio of 1:1 to receive Lipo-MIT or mitoxantrone hydrochloride injection (MIT) intravenously. The dosage was 20 mg/m 2 for Lipo-MIT and 14 mg/m 2 for MIT, once every four weeks (i.e., one treatment cycle). The primary endpoint was objective response rate(ORR). The secondary endpoints were progression free survival (PFS) and safety. Results: From Oct 2015 through Jul 2017, 60 patients were randomized to Lipo-MIT group (n = 30) or MIT group (n = 30). The Median (Q1,Q3) age was 56.0 (41.0,62.0) years in Lipo-MIT group and 54.5 (44.0,62.0) years in MIT group. Nineteen patients in Lipo-MIT group and 23 in MIT group received &lt; 4 cycles of treatment, 11 patients in Lipo-MIT group and 7 in MIT group were treated for 4 or more cycles. When Lipo-MIT group was compared with MIT group, ORR was 13.3% (4/30) and 6.7% (2/30), disease control rate (PR+SD) was 50% (15/30) and 30% (9/30), median PFS was 2.30 (95% CI: 1.74-3.91) and 1.86 (95% CI: 1.74-2.40) months ( P&gt; 0.05). Lipo-MIT showed significantly lower incidence of all-grade white blood cell decreased (86.7% vs 96.7%), neutrophil count decreased (80.0% vs 96.7%), conjugated bilirubin increased (53.3% vs 56.7%), aspartate aminotransferase increased (40.0% vs 53.3%), and troponin T increased (3.3% vs 36.7%) than MIT, but higher incidence of anemia (76.7% vs 46.7%), skin hyperpigmentation (66.7% vs 3.3%), and platelet count decreased (56.7% vs 53.3%) than MIT. Conclusions: Lipo-MIT provided numerically better ORR, DCR, and PFS than MIT in ABC. Lower incidence of troponin T increased might suggest lower cardiotoxicity of Lipo-MIT. It is worthwhile to further explore the clinical utility of Lipo-MIT in ABC. Clinical trial information: NCT02596373 .
Cell-free DNA and exoDNA analysis in metastatic colorectal cancer patients (mCRC).
Authors: Antonio Galvano, Marta Castiglia, Aurelia Guarini, Valerio Gristina, Sofia Cutaia, Viviana Bazan, Antonio Russo, Ignazio UGO Carreca
Journal: Journal of Clinical Oncology (2020)

e16093 Background: Liquid biopsy is a growing field in translational cancer research. Two of the most studied liquid biopsy biomarkers are cell-free DNA (cfDNA) and exosomes, nano-sized vesicles that transport protein and nucleic acids including DNA (exoDNA). Therefore, both cfDNA and exoDNA are potentially useful to investigate the molecular landscape of tumor with a minimally invasive approach. Here we investigate the prognostic and predictive role of both cfDNA and exoDNA in mCRC using Next Generation Sequencing (NGS) analysis. Methods: From July 2017 to September 2018, samples of 40 mCRC patients were collected at the Medical Oncology of the AOUP Paolo Giaccone of Palermo. Blood samples were collected in EDTA-tubes before chemotherapy infusion (T1), at the first instrumental evaluation (T2) and every 2-3 months (T3). Plasma was used to isolate cfDNA and exosomes using the QIAamp Circulating Nucleic Acid and ExoEasy Maxi Kit respectively. ExoDNA was isolated through the QIAamp DNA micro kit. NGS analysis was conducted on IonS5 with AmpliSeq Cancer Hotspot Panel v2, which includes hotspot regions of 50 cancer-related genes. Results: Patients with cfDNA concentration &gt; 0.47ng/μl have worse PFS compared with those with &lt; 0.47 ng/μl cfDNA level. NGS analysis from 16 cfDNA samples showed a total of 292 mutations, with a median of 5 non-synonymous mutations in T1 vs. 8 non-synonymous mutations in T2 sample. We report an inverse and significant correlation between non-synonymous mutations count and disease-specific survival (DSS). Only 2 cfDNA samples carried KRAS mutations, despite it were previously reported in 5 paired tissue samples. An interesting result emerged from exoDNA sequencing of CRC20. KRAS mutation was identified in T1 exoDNA but not in the paired cfDNA samples, suggesting that exoDNA is able to intercept KRAS mutation earlier than cfDNA. Conclusions: cfDNA analysis could be a useful tool for better patients’ stratification. exoDNA could allow an early interception of disease recurrence that could be explained by the ability of exosomes to protect their cargo from degradation.
A pilot study of levetiracetam as a sensitizer of temozolomide for newly diagnosed glioblastoma: A prospective, open-label, phase II study (KBTS-1601 study).
Authors: Chae-Yong Kim, Kihwan Hwang, Jong Hee Chang, Seok-Gu Kang, Tae-Young Jung, Jeong Hoon Kim, Se-Hyuk Kim, Shin-Hyuk Kang, Yong-Kil Hong, Tae Min Kim, Byung Se Choi, YuJung Kim, Ghee Young Choe
Journal: Journal of Clinical Oncology (2020)

2560 Background: We evaluated the survival benefit of levetiracetam as a chemosensitizer of temozolomide for patients with newly diagnosed glioblastoma. Methods: This was an open-label, multicenter, phase II study (NCT02815410). Eligible patients were aged 18 years or older and had newly diagnosed glioblastoma with an ECOG performance status of 0-2. All patients received radiotherapy with concurrent temozolomide (75 mg/m 2 /day) followed by adjuvant temozolomide (150-200 mg/m 2 /day for 5 days during six 28-day cycles). The first dose of levetiracetam was given just after the surgery at 250mg orally twice a day and increased up to 500mg twice a day prior to radiation. This prospective study was designed to test whether levetiracetam in conjunction with temozolomide improved survival. The historical control group was based on data from a study by Gwak et al. for Korean patients with newly diagnosed glioblastoma with a median overall survival(OS) of 17.5 months and a median progression-free survival (PFS) of 10.1 months. Results: Forty-six patients were enrolled between August 2016 and January 2019. The median follow-up duration was 24.9 months (range, 7.9-35.5). All patients completed standard radiation therapy with temozolomide, and 39 (84.8%) patients completed six cycles of adjuvant temozolomide. Median overall survival (OS) was 30.0 months, and median PFS was 15.0 months. OS at 6, 12, and 24 months was 100%, 91.3%, and 60.7%, respectively. PFS at 6, 12, and 24 months was 93.2%, 65.3%, and 22.6%, respectively. Conclusions: Addition of levetiracetam during concurrent and adjuvant temozolomide along with radiotherapy in patients with newly diagnosed glioblastoma may result in improved outcomes compared to historical data and merits further study. Clinical trial information: NCT02815410 .
Effect of managed health education on psychological and nutritional status of patients with HBV-related cirrhosis and ascites
Authors: Guang-bin Zhao, Yu-ni Zhang, Xiao-juan He
Journal: BMJ (2013)

Objective
To evaluate the effect of managed health education on psychological and nutritional status of patients with HBV-related cirrhosis and ascites.


Methods
One hundred and twenty one patents with decompensated HBV-related cirrhosis were enrolled for health education and randomly divided into two groups: 61 patients received managed health education (trial group) and 60 received conventional health education (control group). In control group patients were informed with their condition and diet note by medical orders. In control group the hepatologists evaluated the baseline condition, nutritional status and quality of life, set up personal files of patients and followed up with communication and counselling periodically from June 2010 to August 2012. The psychological conditions were assessed with self-rating anxiety scale (SAS) and self-rating depression scale (SDS); nutritional status was assessed with triceps skinfold thickness (TSF) and mid-arm muscle circumference (MAMC) and the quality of life was assessed with MOS 36-item shoort from healthy survey (SF-36).


Results
Before health education, there was no statistical difference in the scores of SAS, SDS, TSF, SF-36 and blood Hb, albumin (Alb) levels between two groups. After health education, scores of SAS and SDS were decreased in both groups (P<0.01), however, which in trial group were lower than those in control group (39.9±8.8 vs. 49.0±9.4 and 40.6±8.8 vs. 51.9±10.1 respectively, both P<0.01). The TSF scores and blood Hb and Alb levels in trial group were higher than those in control group (P<0.05). The accumulated scores of 8 dimensions in SF-36 forms in trial group were significantly higher than those in control group (P<0.01).


Conclusion
The managed health education model can better release psychological pressures, decrease mental disorders, elevate nutrition status, promote health and improve quality of life than conventional health education for patients with HBV-related cirrhosis and ascites.


Key words: 
Liver cirrhosis; Patient care management; Psychotherapy, multiple; Quality of life
The effect of aspirin on colorectal cancer incidence in African Americans.
Authors: Oluwadunni Emiloju, Djeneba Audrey Djibo, Jean G Ford
Journal: Journal of Clinical Oncology (2020)

4085 Background: From 2011 to 2016, the incidence and mortality rate of colorectal cancer(CRC) were highest among African Americans(AA), compared to other US racial/ethnic groups. Long-term aspirin use is recommended as a strategy to reduce the risk of CRC. Yet, there is scant information on the chemopreventive effect of aspirin among AA. It is imperative to assess whether the reported chemo-preventive effect also occurs in AA. Our central hypothesis is that aspirin use in AA is associated with a lower incidence of CRC, irrespective of race/ethnicity. Methods: We conducted a secondary analysis, using data from AA participants in the Atherosclerosis Risk in Communities(ARIC) longitudinal study, who did not have CRC at enrollment, from 1987 to 1998. We extracted demographic, clinical and mortality data to compare the incidence of CRC among participants taking aspirin compared to those who were not taking aspirin, stratified by age, tobacco use, and body mass index. All-cause mortality and CRC mortality will also be assessed, and we will use Cox proportional hazard regression to determine the relationship between aspirin use and CRC incidence, and mortality. Results: At baseline in 1987, 15,026 participants enrolled in the ARIC study, 25% of whom were AA, median age 54(range 44-66), including 46.7% who reported using aspirin. We analyzed follow-up data from 10,960 participants in 1996-1998, 20% of whom were AA, and 56.9% of whom were taking aspirin. Non-AA participants were more likely to report using aspirin at baseline and follow-up, compared to AA, 53% vs 30% and 59% vs 50% respectively. After 10years, the total incidence of CRC in AA participants was 1% compared with 1.1% in non-AA(p = 0.7). There was no difference in CRC incidence by aspirin use among all participants, and when stratified by race(among all participants p = 0.81, amongAA p = 0.68, among non-AA p = 0.94). Conclusions: We found no difference in the incidence of CRC among AA compared to Caucasians, by aspirin use. Investigation of consistency and/or dose of aspirin use by race may provide further insights on the relationship between aspirin use and CRC incidence, comparing AA to Caucasians.
Safety of BI 754111, an anti-LAG-3 monoclonal antibody (mAb), in combination with BI 754091, an anti-PD-1 mAb, in patients with advanced solid tumors.
Authors: Melissa Lynne Johnson, Manish R. Patel, Mohamad Cherry, Yoon-Koo Kang, Kensei Yamaguchi, Do-Youn Oh, Maen A. Hussein, Shigehisa Kitano, Shunsuke Kondo, Aaron Richard Hansen, Ivor John Percent, Ben George, Edward Arrowsmith, Manabu Morimoto, Christine Duffy, Miaomiao Ge, Maren Rohrbacher, Mabrouk M. Elgadi, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2020)

3063 Background: LAG-3, an immune checkpoint receptor involved in T-cell regulation, is frequently co-expressed with PD-1. LAG-3 and PD-1 signaling contributes to immune cell exhaustion and reduces the immune response to tumor cells. Dual inhibition of PD-1 and LAG-3 may reactivate the T-cell response better than blockade of either individual pathway. Here, we report combined safety data from 4 trials investigating BI 754111, an anti-LAG-3 mAb, in combination with BI 754091, an anti-PD-1 mAb, in patients with advanced solid tumors. Methods: Data from 2 phase I dose-escalation/expansion trials, 1 phase I imaging trial, and 1 phase II trial were included. Eligible patients had advanced and/or metastatic solid tumors with measurable disease and an Eastern Cooperative Oncology Group performance status ≤1. Patients received BI 754111 (intravenously [iv], 4–800 mg) in combination with BI 754091 (iv, 240 mg fixed dose) every 3 weeks (q3w). Patients remained on treatment until progressive disease or unacceptable toxicity. In each trial, safety was assessed by incidence and severity of adverse events (AEs), and graded according to Common Terminology Criteria for AEs, version 5. Results: Overall, 321 patients were treated with BI 754111 in combination with BI 754091 (200 [62%] male; median age, 63 years [range 18–88]). Median treatment exposure was 85 days (range 9–625). Of these patients, 282 (87.9%) had any AE (G≥3 in 99 [30.8%]). 285 patients received the 600 mg recommended phase II dose of BI 754111 plus BI 754091 240 mg q3w. Median treatment exposure in these patients was 74 days (range, 8–590). The table shows the 3 most common AEs and 4 most common immune-related AEs, and their frequency. 21 (7.4%) patients had AEs leading to study drug discontinuation, most commonly infusion-related reactions (IRRs) in 6 (2.1%) patients. Serious AEs (all-cause) occurred in 77 patients (27.0%), most commonly pleural effusion in 6 (2.1%) and deep vein thrombosis in 4 (1.4%) patients. 2 patients (0.7%) experienced an AE resulting in death (cardiac tamponade and acute kidney injury, both related to underlying diseases). Conclusions: The combination of BI 754111 and BI 754091 had a manageable safety profile, similar to other checkpoint inhibitors. Clinical trial information: NCT03156114, NCT03433898, NCT03697304, NCT03780725 . [Table: see text]
International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function
Authors: Katie Leach, Fadil M. Hannan, Tracy M. Josephs, Andrew N. Keller, Thor C. Møller, Donald T. Ward, Enikö Kallay, Rebecca S. Mason, Rajesh V. Thakker, Daniela Riccardi, Arthur D. Conigrave, Hans Bräuner-Osborne
Journal: Pharmacological Reviews (2020)

The calcium-sensing receptor (CaSR) is a class C G protein–coupled receptor that responds to multiple endogenous agonists and allosteric modulators, including divalent and trivalent cations, L-amino acids, <i>γ</i>-glutamyl peptides, polyamines, polycationic peptides, and protons. The CaSR plays a critical role in extracellular calcium (Ca<sup>2+</sup><sub>o</sub>) homeostasis, as demonstrated by the many naturally occurring mutations in the CaSR or its signaling partners that cause Ca<sup>2+</sup><sub>o</sub> homeostasis disorders. However, CaSR tissue expression in mammals is broad and includes tissues unrelated to Ca<sup>2+</sup><sub>o</sub> homeostasis, in which it, for example, regulates the secretion of digestive hormones, airway constriction, cardiovascular effects, cellular differentiation, and proliferation. Thus, although the CaSR is targeted clinically by the positive allosteric modulators (PAMs) cinacalcet, evocalcet, and etelcalcetide in hyperparathyroidism, it is also a putative therapeutic target in diabetes, asthma, cardiovascular disease, and cancer. The CaSR is somewhat unique in possessing multiple ligand binding sites, including at least five putative sites for the "orthosteric" agonist Ca<sup>2+</sup><sub>o</sub>, an allosteric site for endogenous L-amino acids, two further allosteric sites for small molecules and the peptide PAM, etelcalcetide, and additional sites for other cations and anions. The CaSR is promiscuous in its G protein–coupling preferences, and signals via G<sub>q/11</sub>, G<sub>i/o</sub>, potentially G<sub>12/13</sub>, and even G<sub>s</sub> in some cell types. Not surprisingly, the CaSR is subject to biased agonism, in which distinct ligands preferentially stimulate a subset of the CaSR's possible signaling responses, to the exclusion of others. The CaSR thus serves as a model receptor to study natural bias and allostery. <h3>Significance Statement</h3> The calcium-sensing receptor (CaSR) is a complex G protein–coupled receptor that possesses multiple orthosteric and allosteric binding sites, is subject to biased signaling via several different G proteins, and has numerous (patho)physiological roles. Understanding the complexities of CaSR structure, function, and biology will aid future drug discovery efforts seeking to target this receptor for a diversity of diseases. This review summarizes what is known to date regarding key structural, pharmacological, and physiological features of the CaSR.