First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody-Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors.

Purpose: This phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody-drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin.

Patients And Methods: This phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid tumors (0.

Evaluation of the Effect of 5 QT-Positive Drugs on the JTpeak Interval - An Analysis of ECGs From the IQ-CSRC Study.

The JTpeak interval has been proposed as a new biomarker to demonstrate mixed ion channel effects, potentially leading to reduced late-stage electrocardiogram (ECG) monitoring for mildly QT-prolonging drugs. ECG waveforms from the IQ-CSRC study were used. Twenty healthy subjects were enrolled with 6 subjects on placebo and 9 subjects on each of 5 mildly QT-prolonging drugs - moxifloxacin, dofetilide, ondansetron, dolasetron, and quinine - and 1 negative drug, levocetirizine.

Novel Antibody Therapeutics Targeting Mesothelin In Solid Tumors.

Abstract Background: Monoclonal antibodies have become attractive clinical anti-cancer drugs in the last 3 decades due to their targeting specificity and suitable pharmacokinetic properties. Mesothelin is a tumor-associated antigen with limited expression in normal tissues. It is frequently over-expressed on the cell membrane of a number of epithelial malignancies (e.

Clinical pharmacology characterization of RG7112, an MDM2 antagonist, in patients with advanced solid tumors.

Purpose: RG7112, the first selective small-molecule MDM2 antagonist in clinical testing, is a non-genotoxic oral p53 activator. To optimize its dose and schedule, a number of clinical pharmacology characteristics were explored in this multicenter trial in patients with advanced solid tumors.

Method: In part 1, the impact of high-energy/high-fat meal and formulations (crystalline and amorphous) on relative bioavailability was examined in single-dose crossover designs.

Effect of axitinib on the QT interval in healthy volunteers.

Purpose: Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1-3, approved for second-line treatment of advanced renal cell carcinoma (RCC). Preclinical studies did not indicate potential for axitinib-induced delayed cardiac repolarization.

Methods: The effect of axitinib on corrected QT (QTc) prolongation was evaluated with one-stage concentration-QTc response modeling using data from a definitive randomized crossover QT phase I study in healthy volunteers administered one single 5-mg axitinib dose alone or in the presence of steady-state ketoconazole (400 mg once daily).

Cardiac Safety Research Consortium: can the thorough QT/QTc study be replaced by early QT assessment in routine clinical pharmacology studies? Scientific update and a research proposal for a path forward.

The International Conference on Harmonization E14 guidance for the clinical evaluation of QT/QTc interval prolongation requires almost all new drugs to undergo a dedicated clinical study, primarily in healthy volunteers, the so-called TQT study. Since 2005, when the E14 guidance was implemented in United States and Europe, close to 400 TQT studies have been conducted. In February 2012, the Cardiac Safety Research Consortium held a think tank meeting at Food and Drug Administration's White Oak campus to discuss whether "QT assessment" can be performed as part of routine phase 1 studies.

The IQ-CSRC prospective clinical Phase 1 study: "Can early QT assessment using exposure response analysis replace the thorough QT study?".

A collaboration between the Consortium for Innovation and Quality in Pharmaceutical Development and the Cardiac Safety Research Consortium has been formed to design a clinical study in healthy subjects demonstrating that the thorough QT (TQT) study can be replaced by robust ECG monitoring and exposure-response (ER) analysis of data generated from First-in-Man single ascending dose (SAD) studies. Six marketed drugs with well-characterized QTc effects were identified in discussions with FDA; five have caused QT prolongation above the threshold of regulatory concern. Twenty healthy subjects will be enrolled in a randomized, placebo-controlled study designed with the intent to have similar power to exclude small QTc effects as a SAD study.

Prediction of overall survival or progression free survival by disease control rate at week 8 is independent of ethnicity: Western versus Chinese patients with first-line non-small cell lung cancer treated with chemotherapy with or without bevacizumab.

Categorizations of best response observed at week 8 (between week 3 and 14) of first-line treatment in two studies of bevacizumab plus chemotherapy in Western (878 patients) and Chinese (198 patients) patients with non-small cell lung cancer were assessed together with baseline prognostic factors in multivariate parametric models to predict overall survival (OS) and progression free survival (PFS). Predictive performances of the models were assessed by simulating multiple replicates of the studies. Disease control rate (DCR) was the best response categorization to predict OS and PFS.

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol.

Aim: To study the differences in QTc interval on ECG in response to a single oral dose of rac-sotalol in men and women.

Methods: Continuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat.

Evaluation of tumor-size response metrics to predict overall survival in Western and Chinese patients with first-line metastatic colorectal cancer.

Purpose: To assess new metrics of tumor-size response to predict overall survival (OS) in colorectal cancer (CRC) in Western and Chinese patients.

Patients And Methods: Various metrics of tumor-size response were estimated using longitudinal tumor size models and data from two phase III studies that compared bevacizumab plus chemotherapy versus chemotherapy as first-line therapy in Western (n = 923) and Chinese (n = 203) patients with CRC. Baseline prognostic factors and tumor-size metrics estimates were assessed in multivariate models to predict OS.

Effect of ketoconazole on the pharmacokinetics of axitinib in healthy volunteers.

Objective: Axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, is metabolized primarily by cytochrome P450 (CYP) 3A with minor contributions from CYP1A2, CYP2C19, and glucuronidation. Co-administration with CYP inhibitors may increase systemic exposure to axitinib and alter its safety profile. This study evaluated changes in axitinib plasma pharmacokinetic parameters and assessed safety and tolerability in healthy subjects, following axitinib co-administration with the potent CYP3A inhibitor ketoconazole.

Comparison of QTinno, a fully automated electrocardiographic analysis program, to semiautomated electrocardiographic analysis methods in a drug safety study in healthy subjects.

Background: Improved automated methods for electrocardiographic (ECG) analysis are needed, particularly for drug development purposes.

Objectives: This study compared a novel fully automated method for ECG analysis (QTinno; NewCardio, Santa Clara, CA) to 2 semiautomated digital methods: global measurement from the earliest QRS onset to the latest T-wave offset on representative superimposed beats (global) and tangent measurement on 3 consecutive beats in one lead (tangent).

Methods: All 3 methods were used to determine uncorrected and rate-corrected QT interval duration (QT and QTcF) and related metrics in 1422 digital 12-lead ECGs from a phase 1 drug study.

Automatic extraction of ECG strips from continuous 12-lead holter recordings for QT analysis at prescheduled versus optimized time points.

Background: Continuous 12-lead ECG monitoring (Holter) in early-phase pharmaceutical studies is today widely used as an ideal platform to extract discrete ECGs for analysis. The extraction process is typically performed manually by trained readers using commercial Holter processing systems.

Methods: Antares, a novel method for automatic 12-lead extraction from continuous Holter recordings applying minimal noise criteria and heart-rate stability conditions is presented.

Automatic analysis of cardiac repolarization morphology using Gaussian mesa function modeling.

A novel fully automated method for wave identification and extraction from electrocardiogram (ECG) waveforms is presented. This approach implements the combined use of a new machine-learning algorithm and of specified parameterized functions called Gaussian mesa functions (GMFs). Individual cardiac cycle waveforms are broken up into GMFs using a generalized orthogonal forward regression algorithm; each individual GMF is subsequently identified (wave labeling) and analyzed for feature and morphologic extraction.

Investigating the effect of sotalol on the repolarization intervals in healthy young individuals.

Background: The dissociation between a drug-induced increase of the QT interval prolongation and an increased risk for ventricular arrhythmias has been suggested by academic investigators and regulatory agencies. Yet, there are no alternative or complimentary electrocardiographic (ECG) techniques available for assessing the cardiotoxicity of novel compounds. In this study, we investigated a set of novel ECG parameters quantifying the morphology of the T-loop.

Challenges of characterizing proarrhythmic risk due to QTc prolongation induced by nonadjuvant anticancer agents.

Background: Drug-induced QTc prolongation is becoming increasingly important in oncology since novel therapies result in prolonged survival of cancer patients already predisposed to cardiotoxicity.

Methods: We review the challenges of implementing the ICH E14 guidance in oncology and propose an integrated approach to QTc risk assessment of nonadjuvant anticancer agents (NAAs), with quantitative outcome criteria.

Results: We recommend informed use of non-clinical cardiac safety pharmacology results, some degree of robust ECG assessments in early phase studies, a dedicated QTc study in cancer patients conducted at the appropriate time pre-, peri-, or post-approval (with the design and timing agreed upon with regulatory agencies), and ECG monitoring in late-phase studies commensurate with the outcome of previous QTc studies.

Quantitative performance of E-Scribe warehouse in detecting quality issues with digital annotated ECG data from healthy subjects.

The US Food and Drug Administration recommends submission of digital electrocardiograms in the standard HL7 XML format into the electrocardiogram warehouse to support preapproval review of new drug applications. The Food and Drug Administration scrutinizes electrocardiogram quality by viewing the annotated waveforms and scoring electrocardiogram quality by the warehouse algorithms. Part of the Food and Drug Administration warehouse is commercially available to sponsors as the E-Scribe Warehouse.

Analyses of dynamic beat-to-beat QT-TQ interval (ECG restitution) changes in humans under normal sinus rhythm and prior to an event of torsades de pointes during QT prolongation caused by sotalol.

Background: Restitution through intracardiac pacing has been used to assess arrhythmia vulnerability. We examined whether analyses of sequential beat-to-beat QT and TQ interval measures can be used to quantify ECG restitution changes under normal sinus rhythm.

Methods: The QT, R-R and TQ intervals were examined 22.

Impaired T-amplitude adaptation to heart rate characterizes I(Kr) inhibition in the congenital and acquired forms of the long QT syndrome.

Introduction: The QTc interval prolongation is not a perfect surrogate marker of the presence of an increased risk for arrhythmic events. In the search for alternative markers, we investigated the T-amplitude and QT interval adaptation to heart rate (HR) in patients with the congenital long QT syndrome (LQTS) and individuals with sotalol-induced QT prolongation.

Methods And Results: Our investigation is based on the analysis of continuous 12-lead digital Holter recordings in: 49 LQT1 carriers, 25 LQT2 carriers, 37 healthy individuals off drugs and on 160 mg of sotalol, and 21 of them also on 320 mg of sotalol.

Quality assessment of digital annotated ECG data from clinical trials by the FDA ECG Warehouse.

The FDA mandates that digital electrocardiograms (ECGs) from 'thorough' QTc trials be submitted into the ECG Warehouse in Health Level 7 extended markup language format with annotated onset and offset points of waveforms. The FDA did not disclose the exact Warehouse metrics and minimal acceptable quality standards. The author describes the Warehouse scoring algorithms and metrics used by FDA, points out ways to improve FDA review and suggests Warehouse benefits for pharmaceutical sponsors.

Contrasting time- and rate-based approaches for the assessment of drug-induced QT changes.

The authors aim to highlight the pitfalls of different validated methods used for the assessment of drugs' effect on QT duration. Digital 12-lead Holter electrocardiograms were recorded at baseline and after a single dose of sotalol in 39 healthy subjects (age = 27.4 +/- 8.

Lack of effect of DX-619, a novel des-fluoro(6)-quinolone, on glomerular filtration rate measured by serum clearance of cold iohexol.

DX-619 is a novel des-fluoro(6)-quinolone with activity against a broad range of bacterial strains, including methicillin-resistant Staphylococcus aureus. The effects of DX-619 on the glomerular filtration rate (GFR) were evaluated because drug-related increases in serum creatinine levels were observed in studies with healthy volunteers. Forty-one healthy subjects were randomized to receive intravenous DX-619 at 800 mg or placebo once daily for 4 days, and the GFR was directly measured by determination of the clearance of a bolus iohexol injection in 33 subjects who completed the study per protocol.

Implications of methodological differences in digital electrocardiogram interval measurement.

Well-specified recommendations have yet to be established on how electrocardiogram (ECG) interval measurement should be performed by digital on-screen caliper systems to assess drug-induced effect on cardiac repolarization in pharmaceutical clinical trials with adequate precision and reproducibility. Since 1997, the industry has followed the European Committee for Proprietary Medicinal Products Points to Consider by using fully manual measurement of 3 consecutive sinus rhythm PQRST complexes in 1 lead only (typically limb lead II). More recently, semiautomatic measurement performed on representative (median) beats and based on the global leads has been considered.