Electrocardiogram QT Prolongation Research Articles

The efficacy and safety of tinengotinib in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC).

133 Background: Tinengotinib is a spectrum-selective multi-kinase inhibitor that targets cell proliferation, angiogenesis, and immune-oncology pathways by inhibiting Aurora kinases A/B, Janus kinases (JAK), and receptor tyrosine kinases (FGFRs, VEGFRs). It has been reported that the activation of JAK/STAT and fibroblast growth factor receptor (FGFR) signaling drives prostate tumor plasticity. Here we present the preliminary safety and efficacy data of tinengotinib in patients with mCRPC from three early phase clinical trials conducted in the US and China. Methods: Eligible mCRPC patients who have no available standard therapeutic treatment options were enrolled to the three studies. Tinengotinib was given as monotherapy at 8 mg QD, 10 mg QD and 12 mg QD. Efficacy tumor assessments were based on RECIST v1.1 for measurable disease and Prostate Cancer Working Group 3 criteria for non-measurable (bone) disease. PSA50 response was also evaluated. CTCAE v5.0 was used for safety assessments. Results: As of 28AUG2023, 30 patients with mCRPC were treated at dose levels of 8 mg QD (n=1), 10 mg QD (n=19) and 12 mg QD (n=10). Median age was 67 years (range 52-82) with ECOG performance status of 1 in 93% of patients. All patients had at least 2 prior therapies including 77% prior docetaxel, 87% prior abiraterone, and 30% prior enzalutamide. The median follow-up time is 5.4 months. Twenty-two (22) patients were efficacy evaluable, of which 13 were evaluable per RECIST v1.1. Fourteen (14) patients were PSA evaluable. The median radiographic progression-free survival (rPFS) was 5.6 months (95% CI, 3.3-7.3). Overall response rate (ORR) was 46% (6/13) and the disease control rate (DCR) was 85% (11/13). Median duration of response (DoR) was 3.0 months. The PSA50 response rate was 50% (7/14). Treatment-related adverse events (TRAEs) occurred in 28 patients (93%). The most common TRAEs (≥20%) included blood thyroid stimulating hormone increase (43%), anemia (37%), hypertension (27%), aspartate aminotransferase increase (23%), electrocardiogram QT prolongation (20%) and white blood cell count decrease (20%). Conclusions: Tinengotinib safety profile was tolerable and manageable. The preliminary efficacy data showed promising clinical benefit of tinengotinib monotherapy in patients with heavily pretreated mCRPC. Further study of tinengotinib in this disease is warranted. Clinical trial information: NCT03654547 , NCT04742959 , NCT05253053 .

A multicenter, open-label, single-arm phase 1/2 study to evaluate the safety and efficacy of FCN-159 in pediatric participants with neurofibromatosis type 1.

10023 Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disease characterized by multiple progressive tumor and non-tumor manifestations, with abnormal activating MAPK pathway. Plexiform neurofibromas (PN) presents in 20-50% of NF1 patients (pts) and may cause serious complications. Selumetinib was approved for pediatric pts with NF1-related PN in US and EU, but therapeutic options remain limited in China. FCN-159 is a highly potent selective anti-tumorigenic inhibitor of MEK1/2, potentially effective in NF1-related PN. Methods: This multi-center, open-label phase1/2 clinical trial is the first-in human study to assess safety and efficacy in pediatric pts with NF1-related PN. The primary objective was to determine the dose limiting toxicity (DLT) and recommended phase 2 dose (RP2D) in the dose escalation, followed by a dose expansion phase 2 to evaluate safety and efficacy. The starting dose in pediatric pts was determined according to the adults in the dose-escalation phase (previously published in ASCO 2022, abstract no. 3011). Here, we first present the safety and efficacy results in pediatric participants. Results: As of data cut-off (November 21, 2022), 65 pts were enrolled, 19 pts in phase 1 and 45 pts in phase 2. A dose of 4 mg/m2 (10 pts) and 5 mg/m2 (9 pts) were evaluated in phase 1 and no DLT was observed. Pediatric pts in the 5 mg/m2 cohort achieved similar exposure to the 8 mg adult cohort. AUC simulation from population PK model at different BSA ranges were also similar to the adults of 8 mg. Therefore, the RP2D was determined to be 5 mg/m2.Treatment-emergent adverse events (TEAEs) were reported in 62 pts (95.4%). Common TEAEs (≥ 20%) were mouth ulcer (43.1%), sinus arrhythmia (36.9%), upper respiratory tract infection (35.4%), folliculitis (21.5%), paronychia (21.5%), and increased blood creatine phosphokinase (20%). 5 pts (7.7%) experienced grade ≥3 treatment-related AEs (TRAEs), including 2 pts (2/10, 10%) in the 4 mg/m2 group and 3 pts (3/55, 5.5%) in the 5 mg/m2 group. Grade 3 TRAEs were increased aspartate aminotransferase (1.5%), electrocardiogram QT prolongation (1.5%), folliculitis (3.1%), and dermatitis acneiform (1.5%). No grade ≥ 4 TRAEs were observed. 2 pts (3.1%) reported treatment-related serious adverse events (one case of rhabdomyolysis and dermatitis acneiform each). TEAEs led to dose interruption (26.2%), and discontinuation (1.5%). No reported TEAE led to dose reduction or death. Of the 19 pts with at least one tumor assessment data after baseline, 8 (42%) pts had partial response, 11 (57.8%) with stable disease and none with disease progression. The median DOR could not be evaluated. Conclusions: Overall, FCN-159 was well-tolerated and demonstrated promising anti-tumor activity in pediatric participants with NF1-related PN. Long-term efficacy and safety follow-up are ongoing. Clinical trial information: NCT04954001 .

Analysis of hydroxychloroquine adverse events in COVID-19 patients reported throughout Iraqi pharmacovigilance center in VigiBase™: A study based on WHO database

Background: Hydroxychloroquine is a long-used medication, most commonly used to treat and prevent malaria, that also has anti-inflammatory and antiviral characteristics. Therefore, specialists have shown interest in the underlying mechanism of its antiviral activity. In vitro experiments have demonstrated its efficiency against SARS coronavirus, and in vitro and in vivo research on coronavirus disease 2019 (COVID-19) is being conducted. We aimed to investigate reports on adverse events of hydroxychloroquine submitted to the Iraqi Pharmacovigilance Centre and compare the incidence of these reported adverse events in Iraq to globally reported cases during the COVID-19 pandemic in 2020 using information component (IC)025 values. Methods: The reported adverse events of hydroxychloroquine to the national Pharmacovigilance database, VigiBase™ a WHO global database of reported potential side effects of medicinal products, were investigated qualitatively (age, sex, and severity) and quantitatively (using IC025) as a measure of the existence of new/altered safety information associated with hydroxychloroquine. Results: A total of 132 reports were found, with women representing 37.1% and men representing 60.6% of cases, while the rest were unidentified, with the predominant age groups ranging from 18–44 years old accounting for 47.4% of cases. The most reported adverse events were upper (17%) and lower abdomen pain (21%), nausea (14%), diarrhea (13%), and electrocardiogram (ECG) QT prolongation (13%). There were 44 different drug-adverse reaction pairings in which the adverse reaction reports included more than one event. The IC025 value for the most widely reported adverse events showed a positive comparable value for upper (2/0.3) and lower abdominal pain (1.8/-0.0), palpitation (1.6/-0.4), and dyspepsia (1.1/0.6). There was a decreased value for IC025 in cases of ECG QT prolongation (3.5/5), diarrhea (0.3/0.8), abdominal discomfort (0.1/2), and oral fungal infection (-0.4/0.6). Conclusions: The IC025 helped determine the higher reporting rate of adverse events compared to the average global rates.

Automatic Detection of Q-T Interval in Electro-cardiograph using MATLAB

While measurement of QT prolongation in electrocardiogram (ECG) is important to clinical applications, but it is quite difficult to evaluate the performance of QT measurement algorithms usingclinical ECGs because the real values of the Q-point and T-end point changes are usually unknown and is difficult to detect. This research paper deals with the Abnormality Detection and its analysis using MATLAB tool software. In this paper, abnormity which is in concern is known as QT prolongation. Due to prolongation or extention of QT interval in the ECG graph obtained from abnormal patient, known as QT syndrome is caused. For the analysis purpose, Large number of data has been taken from QT database and MIT-BIH database. Someof the other useful data were also obtained from other useful sources such as ECG wave maven. In this paper, we have dealt only with the detection of QT interval and its detection. A MATLAB algorithm has been generated highest peak comparison method/Thresholding method which in turns detect the Q-wave and T-end point corresponding to its input samples. This algorithm is designed and analyzed with more than 100 samples taken from the various data base sources. It detects onset of the Q-wave and T-end point which in turn is used to calculate QT interval of the analyzed ECG sample. For Future prospects, detection of QT syndrome from a large number of ECG samples via can be done by designing artificial neural network using MATLAB programming. Inputs weights of the ANN must be trained in such a way that output of the ANN should be 1 for QT syndrome and for rest of the condition, output will be 0(including normal and other arrythmia).

A pharmacovigilance study to quantify the strength of association between the combination of antimalarial drugs and azithromycin and cardiac arrhythmias: implications for the treatment of COVID-19.

ABSTRACT Background: Hydroxychloroquine, an antimalarial drug, combined with azithromycin has been considered a potential treatment for COVID-19. However, these drugs may cause electrocardiogram QT prolongation (QTp) and torsade de Pointes (TdP). We examined potential safety signals for these cardiac arrhythmias. Methods: Using the OpenVigil 2.1 MedDRA platform, we mined data from the U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS) from December 2019 to June 2020. We extracted individual case safety reports based on exposures of seven antimalarial drugs, azithromycin, and combinations. All other drugs in FAERS served as controls. Events of interest included QTp and TdP, with associations between drug exposures and events expressed as adjusted Reporting-Odds-Ratios (aRORs) and confidence intervals. The lower end of aROR 95% confidence interval >1 was used as the statistically significant signal detection threshold. Results: QTp safety signals were found for hydroxychloroquine[aROR:11.70 (10.40–13.16)], chloroquine[aROR:18.97 (11.30–31.87)], quinine[aROR:16.66 (10.18–27.25)], atovaquone[aROR:6.91 (4.14–11.56)], azithromycin alone [aROR:28.02 (22.87–34.32)] and hydroxychloroquine + azithromycin [aROR:75.23 (51.15–110.66)]. TdP safety signals were found for hydroxychloroquine [aROR: 5.62 (4.94–6.38)], chloroquine[aROR:49.37 (30.63–79.58)], and hydroxychloroquine + azithromycin[aROR:33.09 (21.22–51.61)]. Conclusion: Hydroxychloroquine/chloroquine and/or azithromycin was associated with QTp/TdP safety signals and their use should be monitored carefully.

Long-Term Cardiac, Vascular, and Hypertension Safety of Bosutinib (BOS) Versus Imatinib (IMA) for Newly Diagnosed Chronic Myeloid Leukemia (CML): Results from the Bfore Trial

Long-Term Cardiac, Vascular, and Hypertension Safety of Bosutinib (BOS) Versus Imatinib (IMA) for Newly Diagnosed Chronic Myeloid Leukemia (CML): Results from the Bfore Trial

Cardiovascular safety in refractory incontinent patients with overactive bladder receiving add-on mirabegron therapy to solifenacin (BESIDE).

Summary Aims/objectives: In the BESIDE study, combination therapy (antimuscarinic [solifenacin] and β3‐adrenoceptor agonist [mirabegron]) improved efficacy over solifenacin monotherapy without exacerbating anticholinergic side effects in overactive bladder (OAB) patients; however, a potential synergistic effect on the cardiovascular (CV) system requires investigation.Methods OAB patients remaining incontinent despite daily solifenacin 5 mg during 4‐week single‐blind run‐in, were randomised 1:1:1 to double‐blind daily combination (solifenacin 5 mg/mirabegron 25 mg, increasing to 50 mg after week 4), solifenacin 5 or 10 mg for 12 weeks. CV safety assessments included frequency of CV‐related treatment‐emergent adverse events (TEAEs), change from baseline in vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate) and electrocardiogram (ECG) parameters.ResultsThe frequency of hypertension, tachycardia and ECG QT prolongation, respectively, was low and comparable across combination (1.1%, 0.3%, 0.1%), solifenacin 5 mg (0.7%, 0.1%, 0.1%), and solifenacin 10 mg groups (0.8%, 0%, 0.1%). Adjusted mean (SE) change from baseline to end of treatment (EoT) in SBP, DBP, and pulse rate with combination (0.07 mm Hg [0.38], −0.35 mm Hg [0.26], 0.47 bpm [0.28]), solifenacin 5 mg (−0.93 mm Hg [0.38], −0.45 mm Hg [0.26], 0.43 bpm [0.28]) and solifenacin 10 mg (−1.28 mm Hg [0.38], −0.48 mm Hg [0.26], 0.27 bpm [0.28]) was generally comparable, with the exception of a mean treatment difference of ~1 mm Hg in SBP between combination and solifenacin monotherapy; SBP was unchanged with combination and decreased with solifenacin monotherapy. Mean changes from baseline to EoT in ECG parameters were generally similar across treatment groups, except for QT interval corrected using Fridericia's formula, which was higher with solifenacin 10 mg (3.30 mseconds) vs. combination (0.49 mseconds) and solifenacin 5 mg (0.77 mseconds).ConclusionThe comparable frequency of CV‐related TEAEs, changes in vital signs and ECG parameters indicates no synergistic effect on CV safety outcomes when mirabegron and solifenacin are combined.

Safety, tolerability, and pharmacokinetics of single and multiple doses of intravenous cixutumumab (IMC-A12), an inhibitor of the insulin-like growth factor-I receptor, administered weekly or every 2 weeks in patients with advanced solid tumors.

Type 1 insulin-like growth factor receptor (IGF-IR) signaling is often dysregulated in cancer. Cixutumumab, a fully human IgG1 monoclonal antibody, blocks IGF-IR and inhibits downstream signaling. The current study determined the recommended dose, safety, and pharmacokinetic (PK) profile of weekly or every-2-week dosing of cixutumumab. Two open-label, multicenter phase I studies evaluated weekly (3-15 mg/kg) or every-2-weeks (6-15 mg/kg) dosing of cixutumumab in patients with advanced solid tumors. Serial blood samples for PK were collected up to 168-336 h (day 8-15) following the first administration of cixutumumab. Efficacy was evaluated as best overall tumor response. A total of 24 and 16 patients were enrolled in the weekly and every-2-week dosing studies, respectively. Treatment-emergent adverse events (≥10%) included hyperglycemia, fatigue, anemia, nausea, and vomiting. Severe adverse events (AE) were infrequent; one serious AE (grade 3 electrocardiogram QT prolongation) was deemed possibly cixutumumab-related (10 mg/kg every-2-weeks). One death occurred due to disease progression (6 mg/kg weekly cohort). Maximum serum concentrations increased with dose. A maximum tolerated dose was not identified; pre-determined target serum minimum concentrations (60 μg/mL) were achieved with ≥6 mg/kg weekly and ≥10 mg/kg every-2-week dosing. Cixutumumab terminal elimination half-life is approximately a week (individual range, t1/2 = 4.58-9.33 days based upon 10 mg/kg every 2 weeks). Overall, stable disease was achieved in 25% of all patients. Cixutumumab was associated with favorable safety and PK profiles. A dosing regimen of 10 mg/kg every 2 weeks was recommended for subsequent disease-focused clinical trials.

455P - Phase I Study of Lee011 (Cdk4/6 Inhibitor) in Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Cyclin D–Cdk4/6 Pathway-Activated Tumors

ABSTRACT Aim: SMARCB1 mutations are observed in the majority of malignant rhabdoid tumors (MRTs) rendering them dependent on cyclin D1 (CCND1) for genesis and survival. Genetic aberrations in CCND1 and CDK4 are frequent in neuroblastoma cell lines. LEE011 is an orally bioavailable, selective inhibitor of CDK4/6 that has demonstrated tumor growth inhibition in MRT and neuroblastoma preclinical models. In this Phase I study, LEE011 is being investigated in patients (pts) with MRT, neuroblastoma, or other cancers with documented cyclin D–CDK4/6–INK4a–Rb pathway aberrations. Methods: Pts (aged 1–21 years) receive escalating once-daily doses of LEE011 on a 3-weeks-on, 1-week-off schedule. Dose escalation is guided by a Bayesian Logistic Regression Model with overdose control principle and real-time PK. Primary objective: MTD and/or recommended dose for expansion (RDE) determination. Secondary objectives: safety, PK, and efficacy. Results: As of April 8, 2014, 22 pts (11 MRT [9 primary central nervous system (CNS) and 2 extra-CNS], 10 neuroblastoma, and 1 CDK4-amplified alveolar rhabdomyosarcoma) have received LEE011: 5 at 280 mg/m2; 9 at 350 mg/m2; 8 at 470 mg/m2. The median age was 5 (1–20) years. Two DLTs were reported: 1 Grade (G)3 fatigue at 280 mg/m2; 1 G4 thrombocytopenia at 470 mg/m2. Study drug-related all-grade AEs (N = 20; ≥20%) included neutropenia (75%), leukopenia (65%), anemia (40%), thrombocytopenia (40%), lymphopenia (35%), vomiting (25%), decreased appetite (20%), electrocardiogram QT prolongation (20%), fatigue (20%), and nausea (20%). G3/4 AEs (>10%) included neutropenia (70%), leukopenia (35%), thrombocytopenia (25%), and lymphopenia (15%). Preliminary PK analysis showed that exposure following 280 and 350 mg/m2 is comparable to equivalent doses in adults and slightly higher at 470 mg/m2. LEE011 is rapidly absorbed with Tmax ranging from 1–4 hrs (median: 2–3 hrs) across dose levels. To date, best response obtained is stable disease. Conclusions: LEE011 demonstrated an acceptable safety profile and dose-dependent PK. Enrollment continues to identify the MTD/RDE and there will be expansion arms for pts with MRT or neuroblastoma at the RDE. Disclosure: S.G. Dubois: is the site PI for industry sponsored clinical trials (Merck and Novartis). He is also the study chair for a trial funded by Millennium; A. Marabelle: is a member of Advisory Boards for Novartis, BMS, Roche/Genentech, Celgene, Bayer, and Flexus Biotech; S. Modak: has served on an advisory board for Novartis for an unrelated drug; R. Kan: is an employee of and holds shares in Novartis Pharma AG A. Matano: is an employee of Novartis Pharma AG; S.G. Bhansali: is an employee of and holds shares in Novartis Pharmaceuticals Corporation; S. Parasuraman: is an employee of and holds shares in Novartis Pharma AG.All other authors have declared no conflicts of interest.

Functional Characterization of a Trafficking-defective HCN4 Mutation, D553N, Associated with Cardiac Arrhythmia

Hyperpolarization-activated cyclic nucleotide-gated channel 4 gene HCN4 is a pacemaker channel that plays a key role in automaticity of sinus node in the heart, and an HCN4 mutation was reported in a patient with sinus node dysfunction. Expression of HCN4 in the heart is, however, not confined to the sinus node cells but is found in other tissues, including cells of the conduction system. On the other hand, mutations in another cardiac ion channel gene, SCN5A, also cause sinus node dysfunction as well as other cardiac arrhythmias, including long QT syndrome, Brugada syndrome, idiopathic ventricular fibrillation, and progressive cardiac conduction disturbance. These observations imply that HCN4 abnormalities may be involved in the pathogenesis of various arrhythmias, similar to the SCN5A mutations. In this study, we analyzed patients suffering from sinus node dysfunction, progressive cardiac conduction disease, and idiopathic ventricular fibrillation for mutations in HCN4. A missense mutation, D553N, was found in a patient with sinus node dysfunction who showed recurrent syncope, QT prolongation in electrocardiogram, and polymorphic ventricular tachycardia, torsade de pointes. In vitro functional study of the D553N mutation showed a reduced membranous expression associated with decreased If currents because of a trafficking defect of the HCN4 channel in a dominant-negative manner. These data suggest that the loss of function of HCN4 is associated with sinus nodal dysfunction and that a consequence of pacemaker channel abnormality might underlie clinical features of QT prolongation and polymorphic ventricular tachycardia developed under certain conditions.