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The purpose of this study was to assess the effect of pevonedistat, a neural precursor cell expressed, developmentally down‐regulated protein 8 (NEDD8)‐activating enzyme inhibitor, on the heart rate‐corrected QT (QTc) interval in cancer patients. Patients were randomized 1:1 to receive pevonedistat 25 or 50 mg/m2 on day 1 and the alternate dose on day 8. Triplicate electrocardiograms were collected at intervals over 0–11 hours and at 24 hours via Holter recorders on days −1 (baseline), 1, and 8. Changes from time‐matched baseline values were calculated for QTc by Fridericia (QTcF), PR, and QRS intervals. Serial time‐matched blood samples for analysis of pevonedistat plasma pharmacokinetics were collected and a concentration–QTc analysis conducted. Safety was assessed by monitoring vital signs, physical examinations, and clinical laboratory tests. Forty‐four patients were included in the QTc analysis. Maximum least square (LS) mean increase from time‐matched baseline in QTcF was 3.2 milliseconds at 1 hour postdose for pevonedistat at 25 mg/m2, while the LSs mean change from baseline in QTcF was −1.7 milliseconds 1 hour postdose at 50 mg/m2. The maximum 2‐sided 90% upper confidence bound was 6.7 and 2.9 milliseconds for pevonedistat at 25 and 50 mg/m2, respectively. Pevonedistat did not result in clinically relevant effects on heart rate, nor on PR or QRS intervals. Results from pevonedistat concentration–QTc analysis were consistent with these findings. Administration of pevonedistat to cancer patients at a dose of up to 50 mg/m2 showed no evidence of QT prolongation, indicative of the lack of clinically meaningful effects on cardiac repolarization. ClinicalTrials.gov identifier: NCT03330106 (first registered on November 6, 2017). [ABSTRACT FROM AUTHOR]

TAK‐931, a novel, selective, small‐molecule inhibitor of cell division cycle 7 has been investigated in multiple clinical trials in patients with advanced solid tumors. An integrated analysis using data from 2 clinical studies assessed effects of TAK‐931 on electrocardiogram QT intervals and heart rate (HR). Pharmacokinetic samples and matched triplicate electrocardiogram data were collected in 48 patients with cancer receiving oral administration of TAK‐931 50 or 80 mg once daily. The relationships between TAK‐931 plasma concentrations and the HR‐corrected QT interval via Fridericia (QTcF) or population (QTcP) and HR were analyzed using linear mixed‐effects models with fixed effects for day and time. At the geometric mean maximum TAK‐931 plasma concentrations after administration of 50 mg, an HR change of 3.40 beats per minute (90%CI, 1.86‐4.80) was predicted. Change in QTcF of −3.41 milliseconds (90%CI, −5.77 to −1.17) and QTcP of −2.02 milliseconds (90%CI, −4.15 to 0.0679) were estimated, indicating there was no effect of TAK‐931 on the QT intervals at a recommended phase 2 dose of 50 mg once daily for 14 days in a 21‐day cycle. [ABSTRACT FROM AUTHOR]

Population pharmacokinetic (PK) and exposure‐safety analyses of alisertib were performed in children enrolled in 2 clinical trials: NCT02444884 and NCT01154816. NCT02444884 was a dose‐finding study in children with relapsed/refractory solid malignancies (phase 1) or neuroblastomas (phase 2). Patients received oral alisertib 45 to 100 mg/m2 as powder‐in‐capsule once daily or twice daily for 7 days in 21‐day cycles. Serial blood samples were collected up to 24 hours after dosing on cycle 1, day 1. NCT01154816 was a phase 2 single‐arm study evaluating efficacy in children with relapsed/refractory solid malignancies or acute leukemias. Patients received alisertib 80 mg/m2 as enteric‐coated tablets once daily for 7 days in 21‐day cycles. Sparse PK samples were collected up to 8 hours after dosing on cycle 1, day 1. Sources of alisertib PK variability were characterized and quantified using nonlinear mixed‐effects modeling to support dosing recommendations in children and adolescents. A 2‐compartment model with oral absorption described by 3 transit compartments was developed using data from 146 patients. Apparent oral clearance and central distribution volume were correlated with body surface area across the age range of 2 to 21 years, supporting the use of body surface area–based alisertib dosing in the pediatric population. The recommended dose of 80 mg/m2 once daily enteric‐coated tablets provided similar alisertib exposures across pediatric age groups and comparable exposure to that in adults receiving 50 mg twice daily (recommended adult dose). Statistically significant relationships (P <.01) were observed between alisertib exposures and incidence of grade ≥2 stomatitis and febrile neutropenia, consistent with antiproliferative mechanism‐related toxicities. [ABSTRACT FROM AUTHOR]

Background: The purpose of this prospective study was to explore the influence of both preoperative three‐dimensional (3D) reconstruction and intraoperative preservation of the bronchial artery (BA) on postoperative cough after thoracoscopic lobectomy. Methods: A total of 60 patients who had received a combination of thoracoscopic lobectomy and systematic lymph node dissection were included in this study. They were divided into two groups, namely the BA preservation group (Group A), and conventional surgical treatment group (Group B). In group A, we used Exoview software for 3D reconstruction of the BA before the operation and the BA was preserved during the operation. 3D reconstruction of the BA was not performed before surgery in group B. The incidence of postoperative cough, the Mandarin Chinese version of the Leicester cough questionnaire (LCQ‐MC), physiological, psychological and social dimensions and total score of the two groups were compared and analyzed. Results: The scores and total scores of LCQ‐MC in group B were lower than those in group A one and two months after surgery. There were significant differences between the two groups in physiological and psychological dimensions and total scores (p < 0.05), but there was no significant difference in social dimension between the two groups (p > 0.05). The incidence of postoperative cough in group A (16.7%) was lower than that in group B (30%), while the difference was not statistically significant (p = 0.222). Conclusions: Preoperative 3D reconstruction and intraoperative preservation of the BA can reduce the severity of postoperative cough. [ABSTRACT FROM AUTHOR]

The investigational NEDD8‐activating enzyme inhibitor pevonedistat is being evaluated in combination with azacitidine versus single‐agent azacitidine in patients with higher‐risk myelodysplastic syndrome (higher‐risk MDS), higher‐risk chronic myelomonocytic leukemia (higher‐risk CMML), or low‐blast acute myeloid leukemia (AML) in a Phase 3 trial PANTHER. To support Asia‐inclusive global development, we applied multiregional clinical trial (MRCT) principles of the International Conference on Harmonisation E17 guidelines by evaluating similarity in drug‐related and disease‐related intrinsic and extrinsic factors. A PubMed literature review (January 2000–November 2019) supported similarity in epidemiology of higher‐risk MDS, AML, and CMML in Western and East Asian populations. Furthermore, the treatment of MDS/AML was similar in both East Asian and Western regions, with the same dose of azacitidine being the standard of care. Median overall survival in MDS following azacitidine treatment was generally comparable across regions, and the types and frequencies of molecular alterations in AML and MDS were comparable. Dose‐escalation studies established the same maximum tolerated dose of pevonedistat in combination with azacitidine in Western and East Asian populations. Pevonedistat clearance was similar across races. Taken together, conservation of drug‐related and disease‐related intrinsic and extrinsic factors supported design of an Asia‐inclusive Phase 3 trial and a pooled East Asian region. A sample size of ~ 30 East Asian patients (of ~ 450 randomized) was estimated as needed to demonstrate consistency in efficacy relative to the global population. This analysis is presented as an exemplar to illustrate application of clinical pharmacology and translational science principles in designing Asia‐inclusive MRCTs. Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Azacitidine is the standard of care for myelodysplastic syndromes/low‐blast acute myeloid leukemia (AML) across Western and East Asian patients. The first‐in‐class small‐molecule inhibitor of NEDD8‐activating enzyme, pevonedistat, has been investigated as a single agent in multiple studies of hematologic and nonhematologic malignancies and in combination with azacitidine in elderly patients with untreated AML. WHAT QUESTION DID THIS STUDY ADDRESS?By applying clinical pharmacology and translational science and International Conference on Harmonisation E17 principles, this study designed an East Asian‐inclusive global pivotal Phase 3 trial of pevonedistat, taking into consideration drug‐related and disease‐related intrinsic and extrinsic factors. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?These analyses provide scientific rationale for Asia‐inclusive globalization of the pivotal, Phase 3 PANTHER trial and for pooling clinical data across the East Asian region for assessing consistency in efficacy. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?We developed a framework to facilitate efficient global clinical development of investigational therapies for rare cancers and orphan diseases in Asia‐inclusive multiregional clinical trials. [ABSTRACT FROM AUTHOR]

Metabolic fitness of T cells is crucial for immune responses against infections and tumorigenesis. Both the T cell receptor (TCR) signal and environmental cues contribute to the induction of T cell metabolic reprogramming, but the underlying mechanism is incompletely understood. Here, we identified the E3 ubiquitin ligase Peli1 as an important regulator of T cell metabolism and antitumor immunity. Peli1 ablation profoundly promotes tumor rejection, associated with increased tumor‐infiltrating CD4 and CD8 T cells. The Peli1‐deficient T cells display markedly stronger metabolic activities, particularly glycolysis, than wild‐type T cells. Peli1 controls the activation of a metabolic kinase, mTORC1, stimulated by both the TCR signal and growth factors, and this function of Peli1 is mediated through regulation of the mTORC1‐inhibitory proteins, TSC1 and TSC2. Peli1 mediates non‐degradative ubiquitination of TSC1, thereby promoting TSC1‐TSC2 dimerization and TSC2 stabilization. These results establish Peli1 as a novel regulator of mTORC1 and downstream mTORC1‐mediated actions on T cell metabolism and antitumor immunity. Synopsis: The mTORC1 signaling pathway mediates metabolic reprograming and effector function of activated T cells, which is important for antitumor immunity. TSC1 ubiquitination by E3 ubiquitin ligase Peli1 negatively regulates mTORC1 activation and controls glycolytic metabolism and antitumor effector function of T cells. Peli1 negatively regulates activation of the metabolic kinase mTORC1.Peli1 mediates K63 ubiquitination of mTORC1‐inhibitory protein TSC1 and promotes TSC1/TSC2 complex stability.Peli1 deletion promotes the metabolic activities of T cells.Peli1 deficiency in mice promotes antitumor immunity. [ABSTRACT FROM AUTHOR]

Machine learning (ML) was used to leverage tumor growth inhibition (TGI) metrics to characterize the relationship with overall survival (OS) as a novel approach and to compare with traditional TGI‐OS modeling methods. Historical dataset from a phase III non‐small cell lung cancer study (OAK, atezolizumab vs. docetaxel, N = 668) was used. ML methods support the validity of TGI metrics in predicting OS. With lasso, the best model with TGI metrics outperforms the best model without TGI metrics. Boosting was the best linear ML method for this dataset with reduced estimation bias and lowest Brier score, suggesting better prediction accuracy. Random forest did not outperform linear ML methods despite hyperparameter optimization. Kernel machine was marginally the best nonlinear ML method for this dataset and uncovered nonlinear and interaction effects. Nonlinear ML may improve prediction by capturing nonlinear effects and covariate interactions, but its predictive performance and value need further evaluation with larger datasets. [ABSTRACT FROM AUTHOR]

Aims: A population pharmacokinetic (PK) analysis was conducted to quantify the impact of patient‐specific and concurrent medication factors on pevonedistat PK. Methods: Data were pooled from 6 clinical studies consisting of 335 patients with solid tumours or haematological malignancies administered pevonedistat alone or in combination with azacitidine, docetaxel, carboplatin + paclitaxel, or gemcitabine. Model development and covariate analysis followed standard methods. Parameters and bootstrap 95% confidence intervals were estimated using nonlinear mixed‐effects modelling. The final model was evaluated using visual predictive checks and other goodness‐of‐fit criteria. Results: A linear 2‐compartment model best described pevonedistat PK. The final model included the effect of body surface area (BSA) on clearance (CL and Q) and volume of distribution of pevonedistat, effect of concomitantly administered carboplatin + paclitaxel on CL, and effect of albumin on Q. Race, sex, age, tumour type (haematological vs solid), mild or moderate renal impairment (creatinine clearance ≥30 mL/min), or mild hepatic impairment, had no impact on pevonedistat PK. Conclusions: The clinical PK profile of pevonedistat is comparable in patients with solid tumours or haematological malignancies. All PK parameters exhibited ≥20% change over the observed BSA range (1.38–3 m2) with CL ranging from 75.5 to 208% of the reference value, with simulations supporting BSA‐based dosing to minimize interindividual variability in drug exposures. Concurrent administration of carboplatin + paclitaxel decreased pevonedistat CL by approximately 44%, while coadministration with azacitidine, gemcitabine or docetaxel did not alter pevonedistat CL. No other factors were identified as influencing pevonedistat PK. [ABSTRACT FROM AUTHOR]

This clinical trial was designed to evaluate the effect of moderate or severe hepatic impairment on the single‐dose pharmacokinetics (PK) of the investigational anticancer agent, alisertib, in adult patients with advanced solid tumors or lymphoma. Patients with normal hepatic function (total bilirubin and alanine transaminase [ALT] ≤ upper limit of normal [ULN]), moderate hepatic impairment (1.5 × ULN < total bilirubin ≤ 3 × ULN, with any ALT) or severe hepatic impairment (total bilirubin > 3 × ULN, with any ALT), received a single 50‐mg oral dose of alisertib. Blood samples for PK were collected up to 168 hours postdose. Predose samples were also used to assess alisertib plasma protein binding. Patients could continue to receive alisertib for 7 days in 21‐day cycles (50, 30, or 10 mg twice daily for normal hepatic function, moderate hepatic impairment, and severe hepatic impairment, respectively). Alisertib was approximately 99% protein bound in all hepatic function groups. Alisertib exposure was similar in moderate and severe hepatic impairment groups, but higher than the normal hepatic function group. The geometric least‐squares mean ratios (90% confidence intervals) for unbound alisertib area under the curve extrapolated to infinity for moderate/severe impairment groups versus the normal hepatic function group was 254% (184%, 353%). Patients with moderate or severe hepatic impairment have approximately 150% higher unbound alisertib exposures compared with patients with normal hepatic function. An approximately 60% reduction of the starting dose of alisertib in patients with moderate/severe hepatic impairment is recommended based on pharmacokinetic considerations. [ABSTRACT FROM AUTHOR]

Aims: This phase I study evaluated the effects of the moderate cytochrome P450 (CYP) 3A inhibitor fluconazole and the strong CYP3A/P‐glycoprotein (P‐gp) inhibitor itraconazole on the pharmacokinetics of the investigational neural precursor cell expressed, developmentally downregulated 8 (NEDD8)‐activating enzyme inhibitor pevonedistat in patients with advanced solid tumours. Methods: Patients received single doses of intravenous pevonedistat 8 mg m−2, alone and with fluconazole (loading: 400 mg; maintenance: 200 mg once daily), or pevonedistat 8, 15 or 20 mg m−2, alone and with itraconazole 200 mg once daily. Serial blood samples for pevonedistat pharmacokinetics were obtained pre‐ and post‐infusion on days 1 (alone) and 8 (with fluconazole/itraconazole). After completing the pharmacokinetic portion, patients remaining on study received pevonedistat with docetaxel or carboplatin and paclitaxel. Results: The ratios of geometric mean area under the concentration–time curves (n; 90% confidence interval) of pevonedistat in the presence vs. absence of fluconazole or itraconazole were 1.11 (12; 1.03–1.19) and 1.14 (33; 1.07–1.23), respectively. Fifty patients (98%) experienced at least one adverse event (AE), with maximum severity of grade 1–2 in 28 patients (55%) and of grade ≥3 in 22 patients (43%). The most common drug‐related AEs were vomiting (12%), diarrhoea (10%) and nausea (8%). No new safety findings were observed for pevonedistat. Conclusions: Fluconazole or itraconazole had insignificant effects on pevonedistat pharmacokinetics, indicating minor contributions of CYP3A/P‐gp to pevonedistat clearance. The safety profile of single doses of pevonedistat plus steady‐state fluconazole or itraconazole was consistent with prior clinical experience, with no new safety signals observed. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a refractory malignant tumor with poor prognosis, limited chemotherapeutic efficacy, and only about 5% of 5‐year survival rate. We generated a dual‐targeting ligand‐based lidamycin (DTLL) to investigate its efficacy against pancreatic cancer after preparing its precursor, DTLP. DTLP was shown specifically binding to EGFR and HER2 on cell surface, followed by endocytosis into cytoplasm of pancreatic cancer cells. DTLL significantly promoted apoptosis and cell cycle arrest at G2/M stages and inhibited cell proliferation. Pancreatic tumors of either MIA‐paca‐2 cell line‐derived (CDX) or patient‐derived xenograft (PDX) mouse models were significantly regressed in response to DTLL. It suggested that DTLL might be a highly potent bispecific antibody‐drug conjugate (ADC)‐like agent for pancreatic cancer therapy. LDM is known to function as an antitumor cytotoxic agent by its induction of DNA damage in cancer cells, therefore, DTLL, as its derivative, also showed similar cytotoxicity. However, we found that DTLL might reverse the AKT/mTOR feedback activation induced by LDM at the first time. The results from both in vitro and in vivo experiments suggested that DTLL enhanced DNA damage via EGFR/HER2‐dependent blockage of PI3K/AKT/mTOR and PD‐L1 signaling pathways in cancer cells, leading to the inhibition of cell proliferation and immunosurveillance escape from pancreatic tumor. Our studies on DTLL functional characterization revealed its novel mechanisms on internal enhancement of DNA damage and implied that DTLL might provide a promising targeted therapeutic strategy for pancreatic cancer. DTLP showed bispecific binding activities to EGFR/HER‐2 in vitro and in vivo. DTLL showed potent anti‐pancreatic cancer efficacy in CDX and PDX mouse models of human pancreatic cancer 3. DTLL had an antineoplastic effect by inhibited AKT/mTOR and PD‐1/PD‐L1 signal pathways in human pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to determine a correlation between benign and malignant lung solitary pulmonary nodules (SPN), and analyze the association between circulating tumor cell (CTC) levels and different subtypes of lung adenocarcinoma. Methods: A total of 200 patients (80 with SPNs and 120 diagnosed with lung cancer) were included in the study. The CTC levels were quantified by identifying the folate receptor on the surface of tumor cells; clinical tumor specific markers were detected by biochemical immunization. The content of peripheral blood CTCs in benign and malignant lung SPN patients was detected and the differences in preoperative CTC levels in different pathological subtypes were analyzed. Based on the collected data, receiver operating characteristic curves were calculated and the rate of lung cancer was predicted. Results: The peripheral blood CTC levels in patients with malignant lung SPNs were higher than in patients with benign SPNs. The maximum nodule diameter, carcinoembryonic antigen, and CTC levels were independent risk factors for malignant lung SPNs. The peripheral blood CTC levels in patients with stage III–IV lung adenocarcinoma were higher than in stage I–II patients. The peripheral blood CTC levels in patients with microinvasive and invasive adenocarcinoma were higher than in adenocarcinoma in situ patients. The CTC levels in the peripheral blood of patients with maximum tumor diameter > 2 cm were higher than in patients with tumors < 2 cm. Conclusion: The detection of CTCs can be used as a biomarker for screening SPNs and diagnosing early‐stage lung cancer. Using the combination of CTC levels and CEA significantly improves the efficacy of lung adenocarcinoma diagnosis. [ABSTRACT FROM AUTHOR]

Aims This population pharmacokinetic analysis was conducted to describe quantitatively the regional differences and sources of interpatient variability on the apparent oral clearance of alisertib. Methods A population pharmacokinetic analysis was performed on data from 671 cancer patients in Western countries and in Japan/East Asia to whom alisertib 5-150 mg once or twice daily (b.i.d.) was administered in multiple dosing schedules. The final model was used to simulate alisertib pharmacokinetics in patients in the West and East Asian regions in the single-agent schedule of 7 days of dosing in a 21-day cycle. Exposure-safety relationships for mechanism-related antiproliferative toxicities (neutropenia, mucositis and diarrhoea) were estimated by logistic regression. Results Alisertib pharmacokinetics were described by a two-compartment model with four-transit compartment absorption and linear elimination. The final model included a covariate effect of region on relative bioavailability, with patients in the East Asian region estimated to have a 52% higher bioavailability compared with Western patients. Population simulated exposure at 30 mg b.i.d. in patients in Asia was similar to that at 50 mg b.i.d. in Western patients [geometric mean (coefficient of variation) steady state area under the concentration-time curve over the dosing interval (AUC(0-τ)): 21.4 μM.h (52.3%) and 24.1 μM.h (53.6%), respectively]. Exposure-AE relationships could be described for neutropenia, stomatitis and diarrhoea, supporting the lower dosage of alisertib in Asia for global clinical development. Conclusions Model-based simulations support the achievement of similar alisertib exposures in patients in Asia who are administered a 40% lower dose compared with the Western population, thereby providing a quantitative clinical pharmacology bridging and regional dosing rationale for global drug development. [ABSTRACT FROM AUTHOR]

Background: This study was designed to determine the safety, tolerability, and pharmacokinetics (PK) of alisertib (MLN8237) in combination with docetaxel and to identify a recommended dose for the combination.Methods: Adults with metastatic cancer were treated on 21-day cycles with alisertib (10, 20, 30, or 40 mg) twice daily on days 1 to 7 or days 1 to 5 and with docetaxel (75 or 60 mg/m(2) ) on day 1. The primary objectives were to assess the safety and tolerability of the combination and to determine the recommended phase 2 dose (RP2D) for future studies. Secondary objectives included an efficacy assessment and PK analyses of docetaxel and alisertib.Results: Forty-one patients participated. Eight dose levels were explored with various doses of alisertib and docetaxel. The dose-limiting toxicities were neutropenic fever, neutropenia without fever, stomatitis, and urinary tract infection. The RP2D of this combination was 20 mg of alisertib twice daily on days 1 to 7 and intravenous docetaxel at 75 mg/m(2) on day 1 in 21-day cycles. Eight of the 28 patients (29%) who were efficacy-evaluable had objective responses. These included 1 complete response in a patient with bladder cancer, 6 partial responses in patients with castration-resistant prostate cancer, and 1 partial response in a patient with angiosarcoma. Concomitant administration of alisertib did not produce any clinically meaningful change in docetaxel PK.Conclusions: Alisertib at 20 mg twice daily on days 1 to 7 with intravenous docetaxel at 75 mg/m(2) on day 1 in a 21-day cycle was well tolerated, and the combination demonstrated antitumor activity. Cancer 2016;122:2524-33. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

The oxidative and reductive electrochemistry of DPPH nanoparticles is studied via the nanoimpacts method and with drop-casted layers used to modify an electrode surface. In the former case the currents associated with single NP impacts are used to measure the electron transfer kinetics, whereas in contrast it is shown that the reduced diffusion caused by the overlap of adjacent diffusion layers in the latter case leads to more electrochemically reversible behaviour. [ABSTRACT FROM AUTHOR]

We report population pharmacokinetic, pharmacodynamic, and pharmacokinetic-safety analyses to support phase II/III dose/regimen selection of alisertib, a selective Aurora A kinase (AAK) inhibitor. Phase I studies in adult cancer patients evaluated dosing on Days 1-7 in 21-day cycles or Days 1-21 in 35-day cycles, with corresponding maximum tolerated doses of 50 mg twice daily (BID) and 50 mg QD, respectively. Population pharmacokinetic analyses supported dose- and time-linear pharmacokinetics without identification of clinically meaningful covariates. Exposurerelated increases in skin mitotic index and decreases in chromosomal alignment/spindle bipolarity in tumor mitotic cells confirmed AAK inhibition. Exposures in the 7-day schedule at or near 50 mg BID are expected to result in tumor AAK inhibition based on pharmacodynamic assessment in patient tumors. Exposure-safety analyses of data from patients receiving doses of 5-200 mg/day in the 7-day schedule support a low (~ 7%) predicted incidence of dose-limiting toxicity at 50 mg BID. Taken together, these analyses support a pharmacologically active and acceptably tolerated dose range of alisertib for future clinical development. [ABSTRACT FROM AUTHOR]

The regioselective sulfenylation is performed in an eco-friendly solvent system (iPrOH/H2O) under green, atmospheric conditions without a catalyst. [ABSTRACT FROM AUTHOR]