tbuckley/cabot-search huggingface dataset:
Findings from the Clinical Trials Transformation Initiative IND Safety Reporting Advancement Project.
Authors: Raymond P. Perez
Journal: Journal of Clinical Oncology (2015)

e17636 Background: The 2010 FDA IND Safety Reporting Regulation requires sponsors to review safety data across an IND, analyze data in aggregate, and assess causality of events. This was effective in 2011, but compliance is poor. The CTTI IND Safety Advancement Project aims to understand 1) challenges to investigative site safety report management, 2) sponsor challenges to full implementation, 3) sponsor motivation to change safety reporting practice, and 4) best practices for communicating and managing safety reports. Methods: Safety reports received by the FDA Office of Hematology & Oncology Products over an 8 year period straddling publication and finalization of the Regulation were reviewed (n > 140,000). Two surveys were also conducted: one focused on investigative site report management, and a second on sponsor challenges to full implementation of the Regulation. Surveys were followed by qualitative interviews. Results: FDA data showed no significant change in safety report numbers per IND in response to the Regulation. Investigator site respondents (‘sites’; n = 201) were experienced (median > 10 years), active clinical researchers (median > 30 trials), across all trial phases and types, mainly academic and community sites. Managing IND safety reports was a significant workload: 61% expended > 10 hours staff time per month. Sites noticed no change in report quantity or quality since 2011. Variability in processes, PI engagement, and utility of online safety portals were reported. ‘Sponsor’ (n = 28) respondents included large and small companies, with diverse portfolios and a median > 30 currently active trials across all phases. Although ‘sponsor’ respondents perceived that report volumes were reduced, they objectively noted no change. Conclusions: Both groups noted barriers and suggested improvements, creating opportunities for site and sponsor education, regulatory clarity, and process improvement with potential to enhance safety of oncology trials.
Abstract P211: Temporal Trends and Long-Term Outcomes of Elderly Patients With St-Elevation Myocardial Infarction in a Large Rural Healthcare System
Authors: Catherine P Benziger, Patrick Moran, Richard Mullvain, Rakin Solaiman, Ron Regal, Paul Hitz, Ross Blood, Krysta Kaas, Wilson Ginete
Journal: Circulation (2019)

Background: Limited data about long-term survival in elderly patients after ST-elevation myocardial infarction (STEMI) exists for patients in rural settings. We aimed to evaluate temporal trends in lytic use compared to primary percutaneous coronary intervention (PPCI) in elderly patients after the American Heart Association’s Mission: Lifeline program was implemented. Methods: Retrospective cohort included patients aged &gt;=75 years with STEMI presenting to 2 PCI-capable hospitals (Essentia Health in Duluth, MN and Fargo, ND) between 5/2009 to 12/2017. Cox regression was used for survival analysis and logistic regression for 30-day and 1-year mortality and 30-day readmission. Results were adjusted for age and gender. Results: A total of 358 elderly patients with true STEMI were included (51.1% female, mean age 82.2 years, 61.5% rural). The percentage of elderly patients who received lytics decreased from 20.3% in 2009-2010 to 4.8% in 2016-2017. Median first medical contact (FMC) to device time was 128 min (IQR 84-169) and median positive ECG to device time was 107 min (IQR 78-140). FMC to Device &lt;120 min. was 44.3%; ECG to device &lt;120 min. was 61.6%. There was no difference in survival between lytic and PPCI (HR:1.11, 95%CI:0.67-1.86, p=0.68). Mortality was not significantly different between the recent cohort (2016-2017) compared to early cohort (2009-2010) (p=0.16, HR 1.43 (0.86-2.30). Conclusion: Long-term mortality remains high among elderly patients with STEMI, even among revascularized patients. Prognosis has not significantly changed over the past 8 years despite system changes in treatment strategy.
Changes in treatment patterns among patients receiving at least two targeted therapies for metastatic renal cell carcinoma (mRCC) in the US: A comparison of retrospective chart reviews conducted in 2012 and 2014.
Authors: Jose Ricardo Perez, Sumanta Kumar Pal, James E. Signorovitch, William M. Reichmann, Nanxin Li, Zhimei Liu, Eric Jonasch, Nicholas J. Vogelzang
Journal: Journal of Clinical Oncology (2015)

e15620 Background: Treatment options for mRCC have evolved with the approval of multiple targeted therapies (TTs) including tyrosine kinase inhibitors [TKIs, including sunitinib (SUN), sorafenib (SOR), pazopanib (PAZ), and axitinib (AXI)] and mammalian target of rapamycin inhibitors [mTORis, including everolimus (EVE) and temsirolimus (TEM)]. The objective of this study was to descriptively compare treatment patterns in mRCC in the US among patients (pts) initiating a 2nd TT after a 1st TKI from two retrospective chart review studies conducted in 2012 and 2014. Methods: Retrospective chart reviews were conducted in 2012 and 2014. In each, medical oncologists or hematologists/oncologists were recruited from nationally representative panels to review medical records for their mRCC patients. Pt eligibility criteria included: 1) aged ≥ 18 years; 2) initiated 1st TT with a TKI; 3) initiated 2nd TT during 01/2010-06/2012 (“2012 study”) or 02/2012-01/2013 (“2014 study”) with a different TKI or mTORi. Pt characteristics and treatment sequences were compared between the two studies. Results: Charts were reviewed from 306 and 1173 mRCC pts for the 2012 (mean age 63 years; 36% female; 79% with clear cell RCC) and 2014 studies (mean age 63 years; 33% female; 76% with clear cell RCC), respectively. Among 1st TTs, SUN remained the most common agent and use of PAZ increased over time. Among 2nd TTs, EVE remained the most common agent and use of AXI and SOR increased substantially over time (Table). Among pts treated with EVE as 2nd TT, those who received SUN as 1st TT remained the most common (70% and 73%), but those who received PAZ as 1st TT increased over time (13% and 18%). Conclusions: In two recent chart review studies, SUN and EVE remained the most commonly used 1st and 2nd TT, respectively. Use of 1st TT with PAZ and 2nd TT with AXI and SOR increased over time. Optimal treatment sequences in mRCC warrant further studies. TKI mTORi 1st TT AXI PAZ SOR SUN 2012 study 0% 10% 17% 74% 2014 study 1% 13% 11% 74% 2nd TT AXI PAZ SOR SUN EVE TEM 2012 study 3% 12% 7% 6% 49% 23% 2014 study 11% 14% 22% 8% 28% 18%
Exposure-response analysis from a Phase 2 study of the Syk inhibitor entospletinib in patients with relapsed or refractory hematologic malignancies.
Authors: Shringi Sharma, Feng Jin, Meihua Wu, Michelle Robeson, Esteban Abella-Dominicis, Jeff Porter Sharman, Srini Ramanathan
Journal: Journal of Clinical Oncology (2015)

e13584 Background: Entospletinib (ENTO/GS-9973) is an orally bioavailable, selective, reversible, small molecule spleen tyrosine kinase (Syk) inhibitor. ENTO is currently in a Phase 2 clinical trial in subjects with relapsed or refractory CLL/NHL. Methods: ENTO was administered orally twice a day (BID) at a dose of 800 mg. Plasma concentrations of ENTO were measured on Cycle 1 Day 1 (pre-dose, 1.5 and 4 hours post-dose) and during subsequent cycles (pre-dose). A total of 142 patients provided evaluable pharmacokinetic (PK) data with 1274 plasma concentrations for building the population pharmacokinetic model. Covariates screened for influence on the PK parameters were baseline body weight, BMI, BSA, age, serum creatinine, creatinine clearance, AST, ALT, bilirubin, sex and race. Relationships between model predicted ENTO exposures and early efficacy end points such as tumor size (SPD), overall response rate (ORR) and best overall response (BOR) were evaluated. Efficacy assessments were based on IRC evaluation, with a median tumor assessment follow up time of 1.8 months. Results: ENTO PKwas not affected by any of the baseline covariates evaluated. ENTO exposures (AUC, Cmax and Ctrough) were comparable between CLL and FL patients. Over the range of ENTO exposures (~3 to 4 fold range between midpoint of first vs fourth quartile) no association was observed with SPD, ORR or BOR for the CLL and FL population. Conclusions: ENTO PK was comparable across the CLL and FL population after accounting for demographic, biometric, or disease-relevant covariates. No relevant relationship between exposure and early efficacy was observed, suggesting that ENTO 800 mg BID regimen provided exposures resulting in consistent therapeutic effects. Additional follow up data will be needed to confirm these observations. Clinical trial information: NCT01799889.
Non-viral Delivery of Zinc Finger Nuclease mRNA Enables Highly Efficient In Vivo Genome Editing of Multiple Therapeutic Gene Targets
Authors: Anthony Conway, Matthew Mendel, Kenneth Kim, Kyle McGovern, Alisa Boyko, Lei Zhang, Jeffrey C. Miller, Russell C. DeKelver, David E. Paschon, Barbara L. Mui, Paulo J.C. Lin, Ying K. Tam, Chris Barbosa, Tom Redelmeier, Michael C. Holmes, Gary Lee
Journal: Molecular Therapy (2019)

It has previously been shown that engineered zinc finger nucleases (ZFNs) can be packaged into adeno-associated viruses (AAVs) and delivered intravenously into mice, non-human primates, and most recently, humans to induce highly efficient therapeutic genome editing in the liver. Lipid nanoparticles (LNPs) are synthetic delivery vehicles that enable repeat administration and are not limited by the presence of preexisting neutralizing antibodies in patients. Here, we show that mRNA encoding ZFNs formulated into LNP can enable >90% knockout of gene expression in mice by targeting the TTR or PCSK9 gene, at mRNA doses 10-fold lower than has ever been reported. Additionally, co-delivering mRNA-LNP containing ZFNs targeted to intron 1 of the ALB locus with AAV packaged with a promoterless human IDS or FIX therapeutic transgene can result in high levels of targeted integration and subsequent therapeutically relevant levels of protein expression in mice. Finally, we show repeat administration of ZFN mRNA-LNP after a single AAV donor dose results in significantly increased levels of genome editing and transgene expression compared to a single dose. These results demonstrate LNP-mediated ZFN mRNA delivery can drive highly efficient levels of in vivo genome editing and can potentially offer a new treatment modality for a variety of diseases.
Efficacy of docetaxel and androgen receptor axis-targeted agents in castration-resistant prostate cancer patients with intraductal carcinoma of the prostate.
Authors: Akiyuki Yamamoto, Masashi Kato, Toyonori Tsuzuki, Momokazu Gotoh
Journal: Journal of Clinical Oncology (2019)

150 Background: This study aimed to investigate the efficacy of docetaxel and androgen receptor axis-targeted (ARAT) agents in castration-resistant prostate cancer (CRPC) patients with intraductal carcinoma of the prostate (IDC-P). Methods: We retrospectively identified 311 CRPC patients from June 2002 to February 2016. All patients were initially administered with androgen deprivation therapy (ADT), followed by docetaxel or ARAT (abiraterone or enzalutamide) after progressing to CRPC. The primary outcome of interest was overall survival (OS) from the time of CRPC diagnosis and progression-free survival (PFS) from the time of administration of docetaxel or ARAT. Results: IDC-P was found in 180 of 311 patients. The median OS was 33.4 and 64.0 months with and without IDC-P, respectively (hazards ratio [HR], 2.14; P &lt; 0.001). For the first treatment for CRPC, docetaxel was administered to 71 and 50 patients with and without IDC-P, respectively, with a median OS of 30.4 and 64.0 months, respectively (HR, 2.62; P &lt; 0.001). ARAT was administered to 109 and 81 patients with and without IDC-P, respectively, with a median OS of 45.0 and 69.9 months, respectively (HR, 1.84; P = 0.017). Regarding patients with IDC-P, the OS in patients who were administered with ARAT was longer than that in those administered with docetaxel (HR, 0.58; P = 0.008). The median PFS was 7.5 and 12.1 months with and without IDC-P, respectively (HR, 1.36; P = 0.03). Multivariate analysis showed that the prognostic factors for OS were the presence of IDC-P (HR, 1.91; P &lt; 0.001), and administration of ARAT (HR, 0.66; P = 0.02). Conclusions: The presence of IDC-P is an independent prognostic factor for OS and PFS in CRPC patients. ARAT may prolong OS in CRPC patients with IDC-P.
Cluster-Transition Determining Sites Underlying the Antigenic Evolution of Seasonal Influenza Viruses
Authors: Lijun Quan, Chengyang Ji, Xiao Ding, Yousong Peng, Mi Liu, Jiya Sun, Taijiao Jiang, Aiping Wu
Journal: Molecular Biology and Evolution (2019)

Seasonal influenza viruses undergo frequent mutations on their surface hemagglutinin (HA) proteins to escape the host immune response. In these mutations, a few key amino acid sites are associated with significant antigenic cluster transitions. To recognize the cluster-transition determining sites of seasonal influenza A/H3N2 and A/H1N1 viruses systematically and quickly, we developed a computational model named RECDS (recognition of cluster-transition determining sites) to evaluate the contribution of a specific amino acid site on the HA protein in the whole history of antigenic evolution. In RECDS, we ranked all of the HA sites by calculating the contribution scores derived from the forest of gradient boosting classifiers trained by various sequence- and structure-based features. With the RECDS model, we found out that the sites determining influenza antigenicity were mostly around the receptor-binding domain both for the influenza A/H3N2 and A/H1N1 viruses. Specifically, half of the cluster-transition determining sites of the influenza A/H1N1 virus were located in the vestigial esterase domain and basic path area on the HA, which indicated that the differential driving force of the antigenic evolution of the A/H1N1 virus refers to the A/H3N2 virus. Beyond that, the footprints of substitutions responsible for antigenic evolution were inferred according to the phylogenetic trees for the cluster-transition determining sites. The monitoring of genetic variation occurring at these cluster-transition determining sites in circulating influenza viruses on a large scale will potentially reduce current assay workloads in influenza surveillance and the selection of new influenza vaccine strains.
A randomized phase Ib/II study of nivolumab with or without BMS-986253 in combination with a short course of ADT in men with castration-sensitive prostate cancer (MAGIC-8).
Authors: Matthew Dallos, David Henry Aggen, Jessica Hawley, Emerson A. Lim, Mark N. Stein, William Kevin Kelly, David M. Nanus, Charles G. Drake
Journal: Journal of Clinical Oncology (2019)

TPS329 Background: Androgen deprivation therapy (ADT) is highly effective in castration-sensitive prostate cancer (CSPC) but is associated with significant side effects. Novel strategies to reduce ADT exposure and prolong disease control are needed. ADT initially induces a complex immune infiltrate within prostate tumors, suggesting that immunologic intervention may be more effective at the time of castration. Emerging data suggests that the cytokine interleukin-8 (IL-8) recruits immunosuppressive polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment (TME) of many malignancies, including prostate cancer and serum IL-8 levels correlate with lack of response to anti-PD-1 therapy. We hypothesize that immunotherapy with nivolumab (a PD-1 inhibitor) with or without BMS-986253 (an IL-8 inhibitor) combined with degarelix (an LHRH antagonist) will be safe and promote an anti-tumor immune response that can prolong time to disease relapse in CSPC. Methods: This is a randomized, multicenter, two-arm, phase 1b/2 trial of patients with biochemically-recurrent or low volume metastatic CSPC and a rapidly rising PSA (≤12 months). 60 patients will receive immunotherapy with nivolumab or nivolumab plus BMS-986253 for 24 weeks. 16 weeks of ADT with degarelix will be added after 8 weeks of immunotherapy alone. The primary endpoints are safety and PSA relapse rate 10 months after the initiation of therapy. Secondary endpoints include relapse-free survival (RFS), time to testosterone recovery, rate of metastatic progression and change in PSA with immunotherapy alone. Correlative studies will quantify the systemic immune response through cytokine analysis and peripheral T cell profiling using serum and whole blood specimens collected from all enrolled patients. Pre- and on-treatment biopsies will also be obtained from the subgroup of patients with metastatic disease to further define changes in the TME using RNA-sequencing and quantitative multiplex immunofluorescence. The study is open with 1 patient currently enrolled at the time of submission. Clinical trial information: NCT03689699.
Nuclear receptors: recent drug discovery for cancer therapies
Authors: Linjie Zhao, Shengtao Zhou, Jan-Åke Gustafsson
Journal: Endocrine Reviews (2019)

Nuclear receptors (NRs) are transcription factors actively involved in many aspects of human physiology and pathology, serving as sensors of stimuli, master regulators of downstream molecular events, and hubs governing complex gene regulatory networks. The importance of various members of the NR superfamily in cancer has led to substantial efforts to target them therapeutically. Notably, drugs that block the action of estrogen receptor (ER)α in patients with ERα+ breast cancer or the androgen receptor (AR) in patients with prostate cancer have provided remarkable improvements in survival. However, there is continuing need for novel drugs that target ERα or the AR owing to resistance to established drugs, and there are also promising opportunities for targeting other NRs in cancer. In this review, we provide an overview of NR-based drug discovery in cancer and related resistance mechanisms, focusing on novel strategies for targeting well-established NR targets, including ERα, the AR, the glucocorticoid receptor, and the progesterone receptor, as well as opportunities to target other NRs that are attracting interest in immuno-oncology, such as liver X receptors, retinoic acid-related orphan receptors, and farnesoid X receptors.
Quality-of-care provided to prostate cancer (PC) patients for prevention and treatment of osteoporosis-induced by androgen deprivation therapy (ADT): Results of a chart audit.
Authors: Rehab Chahin, Henriette Breunis, Shabbir M.H. Alibhai
Journal: Journal of Clinical Oncology (2013)

e20622 Background: Men with PC on ADT are at risk of developing decreased bone mineral density (BMD) and osteoporosis, frequently associated with increased risk of fractures and related consequences. Guidelines recommend referral to specialized clinics for bone health care, but the quality of care in osteoporosis clinics and benefits to patients has never been reported. Methods: Charts for 67 consecutive men (mean age 74.2 y) on ADT referred to the osteoporosis clinic at the Toronto General Hospital, Toronto, Canada, between 2010 and 2011, were reviewed by a single reviewer using a structured data abstraction sheet. The following quality of care issues were examined: (a) bone health services provided to PC patients receiving ADT, i.e. screening, preventing, and treating osteoporosis; (b) use of Canadian guidelines and fracture risk assessment during ADT for targeting the appropriate therapy. Results: 56 (83.6%) were receiving continuous ADT and 11 (16.4%) intermittent for a mean duration of 27.4±30.7 months at the time of baseline visit. 19.4% had their first BMD before starting ADT and 50.7% during the first year. At initial consultation, 55.2% were taking &lt;1000 mg calcium daily from all sources, while 26.9% were taking more than 1200 mg; 22.4% were taking Vitamin D ≥ 3 months, 81.8% of them had a blood level of Vitamin D ≥ 75 nmol/L. Based on a validated fracture risk assessment tool (CAROC), the 10-year fracture risk was moderate in 28 (41.8%) and high in 9 (13.4%). 71.4% of the patients with a sedentary lifestyle were advised to increase exercise or were referred to a formal exercise program. Of the 39 (70%) and 24 (39.2%) of patients who were not taking appropriate amounts of calcium and vitamin D, respectively, 100% were recommended to adjust their intake to guideline levels. All the patients with high fracture risk were recommended to take bisphosphonates. Conclusions: The osteoporosis clinic performed a comprehensive assessment and recommended guideline-based bone health care for the vast majority of men on ADT, suggesting a systematic approach to assessing bone health is associated with high rates of guideline-adherent care.
Pharmacist Interventions on Outpatient Leukemia Patients Improve Safety
Authors: Madeline Waldron, Caitlin Siebenaller, Marc Earl, Hetty E. Carraway, Anjali S. Advani, Aziz Nazha, Aaron T. Gerds, Betty K. Hamilton, Ronald Sobecks, Matt Kalaycio, Barb Tripp, Brian P. Hobbs, Sudipto Mukherjee, Mikkael A. Sekeres
Journal: Blood (2018)
Propranolol‐Loaded Mesoporous Silica Nanoparticles for Treatment of Infantile Hemangiomas
Authors: Haiwei Wu, Xuan Wang, Jiawei Zheng, Ling Zhang, Xiaoming Li, Wei‐En Yuan, Xuejian Liu
Journal: Advanced Healthcare Materials (2019)

Abstract Infantile hemangioma (IH) is one of the most common neoplasm of infancy. Although with the potential to involute slowly after proliferation, IH has several subsets that could develop severe complications and lead to functional impairment or permanent disfigurement. In the present study, a novel propranolol (PRN) delivery system is developed that encapsulated in mesoporous silica nanoparticles (MSN). The primary nanoparticles are further treated with polyvinyl alcohol (PVA) to form PVA‐MSN‐PRN nanoparticles. The encapsulation efficiency is 58.8% ± 7.2%, and nanoparticles could release PRN in a controlled‐release way. It is discovered that PVA‐MSN‐PRN could significantly suppress hemangioma stem cell (Hemsc) proliferation, promote Hemsc apoptosis in vitro, and inhibit the growth of hemangiomain xenografts in vivo. A conclusion could be made that this novel nanodrug delivery system has high therapeutic efficacy, low cytotoxicity, low administration frequency, and provides an attractive strategy for efficient IH therapy.