A Phase I Dose-Escalation Study of LY3405105, a Covalent Inhibitor of Cyclin-Dependent Kinase 7, Administered to Patients With Advanced Solid Tumors

Cyclin-dependent kinase inhibitor; Solid tumorsInhibidor de quinasas dependent de la ciclina; Tumors sòlidsInhibidor de quinasas dependiente de la ciclina; Tumores sólidosBackground This study aimed to evaluate the safety, pharmacokinetics (PKs), and preliminary activity of LY3405105, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), in patients with advanced solid tumors. Materials and Methods LY3405105 monotherapy was given once daily (QD; part A1) or thrice weekly (TIW; part A2) starting at 1 and 2 mg orally, respectively, and escalated per a Bayesian design in adult patients. The primary endpoint was safety, and secondary endpoints included PKs and antitumor activity. Results Fifty-four patients were enrolled: 43 in part A1 and 11 in part A2. Seven patients had dose-limiting toxicities, all in part A1 (45 mg: n = 3; 35 mg: n = 3; 25 mg: n = 1). Thirty-five patients (64.8%) reported at least one treatment-related adverse event (TRAE). TRAEs (≥10%) were diarrhea, nausea, fatigue, vomiting, abdominal pain, anemia, asthenia, and decreased platelet count. QD dosing showed sustained exposure with less peak-trough fluctuation compared to TIW dosing. Median time to maximum concentration was 1-2 hours and half-life was 15-19 hours. CDK7-target occupancy in skin and peripheral blood on day 15 was dose-dependent and reached near maximal occupancy of 75% at ≥15 mg QD. The maximum tolerated dose (MTD) was 20 mg QD. Twelve patients in part A1 (27.9%) and 5 patients in part A2 (45.5%) had a best overall response of stable disease. No complete response or partial response was observed. Conclusion The MTD of LY3405105 monotherapy was 20 mg QD. The most common toxicities were gastrointestinal adverse events, myelosuppression, fatigue, and asthenia. Limited clinical activity was observed in this phase I trial, and there are no plans for further development. ClinicalTrials.gov Identifier NCT03770494.This work was supported by Eli Lilly and Company. Employees of Eli Lilly and Company participated in the study design, collection, analysis, and interpretation of the data, writing of this report, and decision to submit this article for publication

Gyro orbit simulations of neutral beam injection in Wendelstein 7-X

Simulations exploring neutral beam operation in Wendelstein 7-X (W7-X) at reduced magnetic field are performed using a newly implemented gyro orbit model in the BEAMS3D code. Operation at field strengths below the nominal 2.5 T are seen as a path to explore both high beta plasmas and as a means to access magnetic configurations not possible at 2.5 T. As the field strength becomes smaller, the gyro radius for 55 keV fast protons grows from ${\sim}1\,\mathrm{cm}$ at 2.5 T to ${\sim}5\,\mathrm{cm}$ at 0.75 T in a device with minor radius ${\sim}50\,\mathrm{cm}$ bringing into question the applicability of the gyro center approximation. To address this a gyro orbit model was implemented in the BEAMS3D code. Agreement is found between the gyro center and gyro orbit models in a circular cross section tokamak equilibrium at high field. A set of W7-X equilibria are assessed with fixed density and temperature profiles but decreasing magnetic field strength (increasing plasma beta). Neutral beam deposition is found to be mostly unaffected with changes in the core of the plasma associated with the Shafranov-shift. In general good agreement is found between gyro orbit and gyro center simulations at 2.5 T. Both models indicate increasing losses with decreasing magnetic field strength with the gyro orbit losses being higher at all field strengths. Gyro orbit simulations to the first wall of W7-X show a change in loss pattern with decreasing magnetic field strength. A preliminary assessment of losses to fast ion loss detectors are made

Biola Hour Highlights, 1974 - 11

Thanksgiving by Lloyd Anderson 1 Peter by Richard McNeely Life\u27s Most Difficult Lesson by Al Sanders The Revelation of Jesus Christ by Lloyd Anderson Panel Discussions with Richard Chase, Charles Feinberg, and Samuel Sutherlandhttps://digitalcommons.biola.edu/bhhs/1010/thumbnail.jp

Maintaining physical activity during head and neck cancer treatment: Results of a pilot controlled trial

BackgroundConcurrent chemoradiotherapy (concurrent CRT) to treat head and neck cancer is associated with significant reductions of weight, mobility, and quality of life (QOL). An intervention focusing on functional exercise may attenuate these losses.MethodsWe allocated patients to a 14‐week functional resistance and walking program designed to maintain physical activity during cancer treatment (MPACT group; n = 11), or to usual care (control group; n = 9). Outcomes were assessed at baseline, and 7 and 14 weeks.ResultsCompared to controls, the MPACT participants had attenuated decline or improvement in several strength, mobility, physical activity, diet, and QOL endpoints. These trends were statistically significant (p < .05) in knee strength, mental health, head and neck QOL, and barriers to exercise.ConclusionIn this pilot study of patients with head and neck cancer undergoing concurrent CRT, MPACT training was feasible and maintained or improved function and QOL, thereby providing the basis for larger future interventions with longer follow‐up. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1086–E1096, 2016Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137577/1/hed24162_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137577/2/hed24162.pd

Macaque models of human infectious disease.

Macaques have served as models for more than 70 human infectious diseases of diverse etiologies, including a multitude of agents-bacteria, viruses, fungi, parasites, prions. The remarkable diversity of human infectious diseases that have been modeled in the macaque includes global, childhood, and tropical diseases as well as newly emergent, sexually transmitted, oncogenic, degenerative neurologic, potential bioterrorism, and miscellaneous other diseases. Historically, macaques played a major role in establishing the etiology of yellow fever, polio, and prion diseases. With rare exceptions (Chagas disease, bartonellosis), all of the infectious diseases in this review are of Old World origin. Perhaps most surprising is the large number of tropical (16), newly emergent (7), and bioterrorism diseases (9) that have been modeled in macaques. Many of these human diseases (e.g., AIDS, hepatitis E, bartonellosis) are a consequence of zoonotic infection. However, infectious agents of certain diseases, including measles and tuberculosis, can sometimes go both ways, and thus several human pathogens are threats to nonhuman primates including macaques. Through experimental studies in macaques, researchers have gained insight into pathogenic mechanisms and novel treatment and vaccine approaches for many human infectious diseases, most notably acquired immunodeficiency syndrome (AIDS), which is caused by infection with human immunodeficiency virus (HIV). Other infectious agents for which macaques have been a uniquely valuable resource for biomedical research, and particularly vaccinology, include influenza virus, paramyxoviruses, flaviviruses, arenaviruses, hepatitis E virus, papillomavirus, smallpox virus, Mycobacteria, Bacillus anthracis, Helicobacter pylori, Yersinia pestis, and Plasmodium species. This review summarizes the extensive past and present research on macaque models of human infectious disease

A Phase II Trial of Prexasertib (LY2606368) in Patients With Extensive-Stage Small-Cell Lung Cancer

Patients with extensive-stage small-cell lung cancer (ED-SCLC) need improved outcomes in the relapsed/refractory setting. This phase II study evaluated the safety and efficacy of prexasertib, a checkpoint kinase 1 inhibitor, in platinum-sensitive and platinum-refractory ED-SCLC. Prexasertib demonstrated response rates of 5.2% in platinum-sensitive and 0% in platinum-refractory ED-SCLC. Prexasertib did not show prespecified efficacy as monotherapy in ED-SCLC. Background: This study assessed the checkpoint kinase 1 inhibitor prexasertib in patients with extensive-stage smallcell lung cancer (ED-SCLC).Patients and Methods: This was a parallel-cohort phase II study of 105 mg/m2 prexasertib once every 14 days for patients who progressed after no more than two prior therapies and had platinum-sensitive (Cohort 1) or platinum-resistant/platinum-refractory (Cohort 2) disease. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Exploratory endpoints included biomarker identification and assessment of an alternative regimen (Cohort 3: 40 mg/m2 days 1-3, 14-day cycle). Results: In Cohort 1 (n = 58), ORR was 5.2%; DCR, 31%; median PFS, 1.41 months (95% confidence interval [CI], 1.31-1.64); and median OS, 5.42 months (95% CI, 3.75-8.51). In Cohort 2 (n = 60), ORR was 0%; DCR, 20%; median PFS, 1.36 months (95% CI, 1.25-1.45); and median OS, 3.15 months (95% CI, 2.27-5.52). The most frequent all-grade, related, treatment-emergent adverse events were decreased neutrophil count (Cohort 1, 69.6%; Cohort 2, 73.3%), decreased platelet count (Cohort 1, 51.8%; Cohort 2, 50.0%), decreased white blood cell count (Cohort 1, 28.6%; Cohort 2, 40.0%), and anemia (Cohort 1, 39.3%; Cohort 2, 28.3%). Eleven patients (19.6%) in Cohort 1 and one patient (1.7%) in Cohort 2 experienced grade ≥3 febrile neutropenia. Prexasertib pharmacokinetics were consistent with prior studies. Cohort 3 outcomes were similar to those of Cohorts 1 and 2. No actionable biomarkers were identified. Conclusion: Prexasertib did not demonstrate activity to warrant future development as monotherapy in ED-SCLC

Arsenite Induced Disruption of Mitosis

Arsenite is a known carcinogen that causes skin, bladder, and liver cancer. However, the mechanism of carcinogenesis is unknown. Arsenite (AsO2 - ) delays entry into mitosis by activation of the G2 checkpoint. Arsenite also induces a mitotic delay in anaphase and is aneuploidogenic in normal diploid human cells (p53(+)). In contrast, arsenite induces mitotic arrest and apoptosis in p53 deficient cells (p53(-)). We hypothesize that arsenite, in the presence of p53, induces the inactivation of cyclinB/cdc2 by cdc2 phosphorylation, leading to the derepression of the mitotic exit network. Cdc2, cdc2-P and cyclin B levels were analyzed as the cells progressed from G2 through mitosis to determine whether the p53-dependent G2 checkpoint pathway plays a role in releasing cells from arsenite induced mitotic arrest. TR9-7 cells are a model human fibroblast line in which p53 expression is regulated exogenously in a tetracycline-off system. TR9-7 cells, expressing and not expressing p53, were synchronized in G2 and released into media containing and not containing sodium arsenite (NaAsO2, 5µM). Western blot analyses were used to monitor whether there were any arsenite-induced differences in the proteins expressed and if these changes were p53 dependent. These analyses showed that arsenite stabilization of cyclin B level is p53 independent. Arsenite stabilizes the phosphorylation of Cdc2 in both p53(+) and p53(-) cells even when cyclin B has diminished. Cdc2-P levels are also stabilized early in p53(+) and p53(-) cells not treated with arsenite yet diminish after the 12th hour release from Hoechst 33342. These results are consistent with the inactivation of cyclinB/cdc2 allowing cells to exit mitosis and escape arsenite induced mitotic arrest