Assessing the incidence and severity of drug adverse events: a Bayesian hierarchical cumulative logit model.

Detection of safety signals based on multiple comparisons of adverse events (AEs) between two treatments in a clinical trial involves evaluations requiring multiplicity adjustment. A Bayesian hierarchical mixture model is a good solution to this problem as it borrows information across AEs within the same System Organ Class (SOC) and modulates extremes due merely to chance. However, the hierarchical model compares only the incidence rates of AEs, regardless of severity. In this article, we propose a three-level Bayesian hierarchical non-proportional odds cumulative logit model. Our model allows for testing the equality of incidence rate and severity for AEs between the control arm and the treatment arm while addressing multiplicities. We conduct simulation study to investigate the operating characteristics of the proposed hierarchical model. The simulation study demonstrates that the proposed method could be implemented as an extension of the Bayesian hierarchical mixture model in detecting AEs with elevated incidence rate and/or elevated severity. To illustrate, we apply our proposed method using the safety data from a phase III, two-arm randomized trial.

Efficacy and Safety of Ceritinib 450 mg/day with Food and 750 mg/day in Fasted State in Treatment-Naïve Patients with ALK+ Non-Small Cell Lung Cancer: Results from the ASCEND-8 Asian Subgroup Analysis.

PURPOSE: Previous report from the ASCEND-8 trial showed consistent efficacy with less gastrointestinal (GI) toxicity in patients with anaplastic lymphoma kinase-rearranged (ALK+) advanced/metastatic non-small cell lung cancer (NSCLC) treated with ceritinib 450-mg with food compared with 750-mg fasted. In this subgroup analysis, we report outcomes in Asian patients of the ASCEND-8 trial. MATERIALS AND METHODS: Key efficacy endpoints were blinded independent review committee (BIRC)-assessed overall response rate (ORR) and duration of response (DOR) evaluated per Response Evaluation Criteria in Solid Tumors v1.1. Other efficacy endpoints were investigator-assessed ORR and DOR; BIRC- and investigator-assessed progression-free survival (PFS) and disease control rate; overall survival (OS). Safety was evaluated by frequency and severity of adverse events. RESULTS: At final data cutoff (6 March 2020), 198 treatment-naïve patients were included in efficacy analysis, of which 74 (37%) comprised the Asian subset; 450-mg fed (n=29), 600-mg fed (n=19), and 750-mg fasted (n=26). Baseline characteristics were mostly comparable across study arms. At baseline, more patients in 450-mg fed arm (44.8%) had brain metastases than in 750-mg fasted arm (26.9%). Per BIRC, patients in the 450-mg fed arm had a numerically higher ORR, 24-month DOR rate and 24-month PFS rate than the 750-mg fasted arm. The 36-month OS rate was 93.1% in 450-mg fed arm and 70.9% in 750-mg fasted arm. Any-grade GI toxicity occurred in 82.8% and 96.2% of patients in the 450-mg fed and 750-mg fasted arms, respectively. CONCLUSION: Asian patients with ALK+ advanced/metastatic NSCLC treated with ceritinib 450-mg fed showed numerically higher efficacy and lower GI toxicity than 750-mg fasted patients.

Ceritinib Efficacy and Safety in Treatment-Naive Asian Patients With Advanced ALK-Rearranged NSCLC: An ASCEND-4 Subgroup Analysis.

INTRODUCTION: In the phase 3 ASCEND-4 study, ceritinib exhibited improved progression-free survival (PFS) by Blinded Independent Review Committee (BIRC) assessment versus the standard first-line chemotherapy in patients with advanced ALK-rearranged NSCLC. Here, we assessed the efficacy and safety of ceritinib in the subgroup of Asian patients from the ASCEND-4 trial. METHODS: Treatment-naive patients with stage IIIB or IV ALK-rearranged nonsquamous NSCLC were randomized in a one-to-one ratio to receive either oral ceritinib 750 mg/day (fasted) daily or intravenous chemotherapy ([cisplatin 75 mg/m2 or carboplatin area under the curve 5-6 plus pemetrexed 500 mg/m2] every three wk, followed by pemetrexed maintenance). The primary end point was PFS by BIRC assessment. RESULTS: Of 376 randomized patients, 158 (42.0%) were Asian (ceritinib arm: N = 76; chemotherapy arm: N = 82). The median time from randomization to the cutoff date (June 24, 2016) was 18.3 months (range = 13.5-34.2) in the Asian subgroup. The median PFS (by BIRC assessment) was 26.3 months (95% confidence interval [CI]: 8.6-not estimable) and 10.6 months (95% CI: 6.7-15.0), with an estimated 34% risk reduction in PFS (hazard ratio = 0.66, 95% CI: 0.41-1.05) in the ceritinib arm versus chemotherapy arm. The most common adverse events of any grade were diarrhea (85.5%), increased alanine aminotransferase and vomiting (73.7% each), and increased aspartate aminotransferase and nausea (69.7% each) in the ceritinib arm, and nausea (49.3%), vomiting (42.7%), and anemia (40.0%) in the chemotherapy arm. CONCLUSION: Ceritinib was effective and safe in treatment-naive Asian patients with advanced ALK-rearranged NSCLC. The findings were largely consistent with that of the overall study population.

First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study.

BACKGROUND: The efficacy of ceritinib in patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is not known. We assessed the efficacy and safety of ceritinib versus platinum-based chemotherapy in these patients. METHODS: This randomised, open-label, phase 3 study in untreated patients with stage IIIB/IV ALK-rearranged non-squamous NSCLC was done in 134 centres across 28 countries. Eligible patients were assigned via interactive response technology to oral ceritinib 750 mg/day or platinum-based chemotherapy ([cisplatin 75 mg/m2 or carboplatin AUC 5-6 plus pemetrexed 500 mg/m2] every 3 weeks for four cycles followed by maintenance pemetrexed); randomisation was stratified by World Health Organization performance status (0 vs 1-2), previous neoadjuvant or adjuvant chemotherapy, and presence of brain metastases as per investigator's assessment at screening. Investigators and patients were not masked to treatment assignment. The primary endpoint was blinded independent review committee assessed progression-free survival, based on all randomly assigned patients (the full analysis set). Efficacy analyses were done based on the full analysis set. All safety analyses were done based on the safety set, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01828099. FINDINGS: Between Aug 19, 2013, and May 11, 2015, 376 patients were randomly assigned to ceritinib (n=189) or chemotherapy (n=187). Median progression-free survival (as assessed by blinded independent review committee) was 16·6 months (95% CI 12·6-27·2) in the ceritinib group and 8·1 months (5·8-11·1) in the chemotherapy group (hazard ratio 0·55 [95% CI 0·42-0·73]; p<0·00001). The most common adverse events were diarrhoea (in 160 [85%] of 189 patients), nausea (130 [69%]), vomiting (125 [66%]), and an increase in alanine aminotransferase (114 [60%]) in the ceritinib group and nausea (in 97 [55%] of 175 patients), vomiting (63 [36%]), and anaemia (62 [35%]) in the chemotherapy group. INTERPRETATION: First-line ceritinib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-rearranged NSCLC. FUNDING: Novartis Pharmaceuticals Corporation.

Phase 2 trial of dovitinib in patients with progressive FGFR3-mutated or FGFR3 wild-type advanced urothelial carcinoma.

BACKGROUND: Second-line treatment options for patients with advanced urothelial carcinoma (UC) are limited. Fibroblast growth factor receptor 3 (FGFR3) is dysregulated in UC by activating mutations or protein overexpression in non-mutant tumours. In this study, the efficacy, pharmacodynamics and safety of dovitinib-a broad-targeted inhibitor of tyrosine kinases, including FGFR3-were evaluated in patients with previously treated advanced UC with and without FGFR3 mutations. METHODS: Forty-four adults with advanced UC who had progressed after one to three platinum-based and/or combination chemotherapy regimens were classified as having mutant (FGFR3(MUT); n=12), wild-type (FGFR3(WT); n=31), or unknown (n=1) FGFR3 status. Patients received 500 mg dovitinib once daily on a 5-days-on/2-days-off schedule. The primary end-point of this two-stage study was the investigator-assessed overall response rate (ORR). RESULTS: Most of the patients were men (75%) and over half of the patients were aged ⩾65 years (61%). All patients had received ⩾1 prior antineoplastic therapy for UC. The study was terminated at the end of stage 1, when it was determined by investigator review that the ORR of both the FGFR3(MUT) (0%; 95% confidence interval [CI], 0.0-26.5) and FGFR3(WT) (3.2%; 95% CI, 0.1-16.7) groups did not meet the criteria to continue to stage 2. The most common grade 3/4 adverse events, suspected to be study-drug related, included thrombocytopenia (9%), fatigue (9%), and asthenia (9%). CONCLUSION: Although generally well tolerated, dovitinib has very limited single-agent activity in patients with previously treated advanced UC, regardless of FGFR3 mutation status. clinicaltrials.gov NCT00790426.

Phase I study of dovitinib (TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor, in advanced or metastatic renal cell carcinoma.

PURPOSE: Signaling through the fibroblast growth factor (FGF) pathway may account for tumor resistance to antiangiogenic therapies targeting the VEGF pathway. Here, dovitinib (TKI258), a potent oral inhibitor of FGF receptor, VEGF receptor (VEGFR), and platelet-derived growth factor receptor tyrosine kinases, is studied in a dose escalation trial. EXPERIMENTAL DESIGN: Patients with advanced or metastatic renal cell carcinoma (RCC) with predominant clear cell histology were treated with oral dovitinib 500 or 600 mg/day (5-days-on/2-days-off schedule). RESULTS: Twenty heavily pretreated patients (median 3 prior regimens) were enrolled, with 16, 11, and 12 patients having previously received at least 1: VEGFR inhibitor, mTOR inhibitor, and immunotherapy, respectively. Fifteen and 5 patients were treated in 500- and 600-mg cohorts, respectively. Three patients experienced dose-limiting toxicities: grade 2 bradycardia (500 mg), grade 4 hypertensive crisis (600 mg), and grade 3 asthenia with grade 2 nausea and vomiting (600 mg). The most common adverse events related to dovitinib were nausea (75%), diarrhea (70%), vomiting (70%), and asthenia (50%), the majority of which were mild (grade 1 or 2), with grade 3 events 5% or less (except asthenia, 15%) and only one grade 4 event (hypertensive crisis). Two patients achieved a partial response (500 mg), and 12 patients had stable disease, including 2 patients with long lasting disease stabilizations (>1 year) in the 500-mg cohort. CONCLUSIONS: Dovitinib was tolerable and showed antitumor activity at a maximum tolerated dose of 500 mg on a 5-days-on/2-days-off schedule in heavily pretreated RCC patients.

Genes induced by a high-oxygen environment in Entamoeba histolytica.

Entamoeba histolytica, although a microaerophilic protozoan parasite, encounters a high-oxygen environment, during invasive amoebiasis. The parasite requires specific regulation of certain proteins to maintain its physiological functions to survive in the more oxygenated condition. Our endeavor was to know how does amoeba adapt itself in a high-oxygen environment. Reactive oxygen species (ROS) was found to accumulate in an increasing concentration within the stressed trophozoites in a time-dependent manner. Increased cytopathic activity was detected at 2h in high-oxygen-exposed E. histolytica lysate compared to lysate of normal E. histolytica trophozoites by Ussing chamber assay. The differential display and semi-quantitative polymerase chain reaction showed overexpression in the mRNA levels of thiol-dependent peroxidase (Eh29), superoxide dismutase (SOD), EhCP5, G protein, HSP70, and peptidylprolyl isomerase at different time periods of oxidative stressed trophozoites compared to normally cultured E. histolytica. Analyses of the up-regulated genes that are associated with stress response, viz., signal transduction, tissue destruction, and oxidative stress management, including enhanced expression of a 29-kDa Eh29, suggest that this organism has several protective mechanisms to deal with oxidative stress during invasion.