QTcF Values Research Articles

Open-label, single-dose, parallel-group study in healthy volunteers to determine the drug-drug interaction potential between KAE609 (cipargamin) and piperaquine.

KAE609 represents a new class of potent, fast-acting, schizonticidal antimalarials. This study investigated the safety and pharmacokinetics of KAE609 in combination with the long-acting antimalarial piperaquine (PPQ) in healthy volunteers. A two-way pharmacokinetic interaction was hypothesized for KAE609 and PPQ, as both drugs are CYP3A4 substrates and inhibitors. The potential for both agents to affect the QT interval was also assessed. This was an open-label, parallel-group, single-dose study with healthy volunteers. Subjects were randomized to four parallel dosing arms with five cohorts (2:2:2:2:1), receiving 75 mg KAE609 plus 320 mg PPQ, 25 mg KAE609 plus 1,280 mg PPQ, 25 mg KAE609 alone, 320 mg PPQ alone, or 1,280 mg PPQ alone. Triplicate electrocardiograms were performed over the first 24 h after dosing, with single electrocardiograms at other time points. Routine safety (up to 89 days) and pharmacokinetic (up to 61 days) assessments were performed. Of the 110 subjects recruited, 99 completed the study. Coadministration of PPQ had no overall effect on exposure to KAE609, although 1,280 mg PPQ decreased the KAE609 maximum concentration (Cmax) by 17%. The group that received 25 mg KAE609 plus 1,280 mg PPQ showed a 32% increase in the PPQ area under the concentration-time curve from 0 to infinity (AUCinf), while the group that received 75 mg KAE609 plus 320 mg PPQ showed a 14% reduction. Mean changes from baseline in the QT interval corrected by Fridericia's method (QTcF) and the QT interval corrected by Bazett's method (QTcB) with PPQ were consistent with its known effects. PPQ but not KAE609 exposure correlated with corrected QT interval (QTc) increases, and KAE609 did not affect the PPQ exposure-QTc relationship. The QTcF effect for PPQ (least-squares estimate of the difference in mean maximal changes from baseline of 7.47 ms [90% confidence interval, 3.55 to 11.4 ms]) was consistent with the criteria for a positive thorough QT study. No subject had QTcF or QTcB values of >500 ms. Both drugs given alone or in combination were well tolerated, with no deaths, serious adverse events (AEs), or severe AEs reported. Most AEs were mild; upper respiratory tract infections, headache, diarrhea, and oropharyngeal pain were most common. PPQ and KAE609 coadministration had no relevant effect on exposure to either agent, and KAE609 did not affect or potentiate the known effects of PPQ on cardiac conduction.

A randomized, placebo- and moxifloxacin-controlled thorough QT study of umeclidinium monotherapy and umeclidinium/vilanterol combination in healthy subjects

IntroductionThe long-acting muscarinic antagonist umeclidinium (UMEC) and the combination of UMEC with the long-acting beta2 agonist vilanterol (VI) are approved maintenance treatments for chronic obstructive pulmonary disease in the US and EU. ObjectivesThis study investigated the effect of UMEC and UMEC/VI on the QT interval corrected using Fridericia's correction (QTcF) following a 10-day treatment period. MethodsRandomized, placebo- and moxifloxacin-controlled, 4-period incomplete block crossover study of healthy non-smokers (n = 103). All treatments were double blind, except for moxifloxacin/moxifloxacin placebo controls which were single blinded. Subjects were randomized to a treatment sequence which consisted of 4 of 5 regimens. Each regimen consisted of once-daily doses on Days 1–10 via the ELLIPTA™ dry powder inhaler and a single tablet on Day 10 of the following: placebo + placebo; placebo + moxifloxacin; UMEC 500 μg + placebo; UMEC/VI 125/25 μg (delivered dose: 113/22 μg) + placebo; UMEC/VI 500/100 μg + placebo. QT interval, additional cardiac parameters, pharmacokinetics, pharmacodynamics and safety were assessed. ResultsNo clinically significant changes from baseline in QTcF occurred with UMEC 500 μg and UMEC/VI 125/25 μg compared with placebo, however, there was a change in QTcF from baseline of 6.4 ms (90% confidence interval [CI]: 4.3, 8.5) at 10 min and 8.2 ms (90%: 6.2, 10.2) at 30 min post dose following UMEC/VI 500/100 μg compared with placebo. On Day 10, categorical analysis demonstrated absolute QTcF values >450–480 ms for UMEC/VI 125/25 μg (1 subject) and moxifloxacin (3 subjects), and a change from baseline QTcF of >30–60 ms for UMEC/VI 125/25 μg, UMEC 500/100 μg and placebo (1 subject each) and moxifloxacin (2 subjects). On Day 10, the mean change from baseline in heart rate was increased with UMEC/VI 125/25 μg and UMEC 500/100 μg compared with placebo with the maximum increase occurring at 10 min post dose (8.4 bpm [90% CI: 7.0, 9.8] for UMEC/VI 125/25 μg; 20.3 bpm [90% CI: 18.9, 21.7] for UMEC/VI 500/100 μg); after this timepoint, heart rate rapidly returned to normal levels. UMEC and VI systemic exposures following UMEC/VI 500/100 μg were >4-fold higher than those following UMEC/VI 125/25 μg. All treatments were generally well tolerated in terms of adverse events, laboratory, vital signs and electrocardiogram data; the proportion of subjects with any adverse event was similar across treatments arms (39–59%).. ConclusionThere was no clinically significant effect on QTcF observed following 10-days' treatment with inhaled UMEC/VI 125/25 μg or UMEC 500 μg compared with placebo. The supratherapeutic dose of UMEC/VI 500/100 μg prolonged QTcF by 6.4 ms (90% CI: 4.3, 8.5) at 10 min and 8.2 ms (90% CI: 6.2, 10.2) at 30 min compared with placebo, following which QTcF interval difference from placebo declined rapidly..

Exposure–response analysis of pertuzumab in HER2-positive metastatic breast cancer: absence of effect on QTc prolongation and other ECG parameters

PurposeThe phase III trial of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel for first-line treatment of HER2-positive metastatic breast cancer included a substudy to determine whether pertuzumab affected the corrected QT (QTc) interval or other electrocardiogram parameters.MethodsTriplicate 12-lead electrocardiogram measurements and serum samples were collected before (–30 and –15 min) and after (0–15 and 60–75 min) pertuzumab/placebo infusions (Cycles 1 and 3), and at 72 h post-infusion (Cycle 1). Fridericia’s correction was applied to QT measurements (QTcF) and change from baseline (ΔQTcF) calculated. Statistical analyses were performed on baseline-adjusted, placebo-corrected QTcF values (ΔΔQTcF). Linear mixed-effects modeling evaluated potential exposure–response relationships between ΔQTcF and observed pertuzumab concentrations.ResultsThirty-seven female patients participated in the substudy. QTcF values in both groups were within the normal range and below critical thresholds of clinical concern. No pertuzumab-treated patient showed abnormal electrocardiogram morphology. In Cycle 1, mean ΔΔQTcF (90 % CI) values at 0–15 min, 60–75 min, and 72 h post-infusion were −6.96 (−13.69, −0.23), −6.35 (−13.57, 0.88), and −4.08 (−12.64, 4.48), all of which were <5 ms, with upper CI limits <10 ms. One Cycle 3 post-infusion mean ΔΔQTcF value exceeded 5 ms. Other electrocardiogram parameters were within normal ranges. Concentration–QTc modeling showed no apparent relationship between ΔQTcF and pertuzumab concentrations.ConclusionsCardiac monitoring and concentration–QTc modeling demonstrated that pertuzumab, combined with trastuzumab and docetaxel, had no clinically relevant effects on QTcF and other electrocardiogram parameters.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-013-2279-6) contains supplementary material, which is available to authorized users.

Open label evaluation of ECG in patients with chronic lymphocytic leukemia (CLL) receiving ibrutinib monotherapy.

7057 Background: Ibrutinib is a first-in-class selective small molecule inhibitor of Bruton’s tyrosine kinase (BTK) under development for the treatment of B-cell malignancies. The aim of this study was to characterize the possible effect of ibrutinib on ECG intervals in patients with CLL. Methods: A Phase Ib/II study (PCYC-1102-CA) of oral dosing of ibrutinib was conducted in patients with treatment-naïve (TN) or relapsed/refractory (R/R) CLL. Patients were enrolled into 6 groups treated with ibrutinib at 420 mg/day or 840 mg/day (n=132). One cycle was 28 days. ECG data were obtained along with the blood samples during Cycle 1. Additional ECG measurement was performed on Day 28 of Cycles 3, 6, 12, 18, and 24 and at the end of study. An interim ECG analysis was performed using the data from R/R patients at 420 mg/day (n=18), TN patients at 420 mg/day (n=20), and R/R patients at 840 mg/day (n=29). For ECG analysis, the pre-dose values on Cycle 1 Day 1 were used as the baseline for each post-dose time-point for all ECG parameters. The QT and RR values for each beat were used for both Fridericia's correction (QTcF) and Bazett's correction (QTcB). The relationship between plasma concentrations of ibrutinib and ΔQTcF (change-from-baseline QTcF) was investigated by a linear mixed-effects modeling approach. Results: Median ages for R/R 420 mg, TN 420 mg, and R/R 840 mg dose groups were 59, 71, and 62 years, respectively. There was no clinically significant change in heart rate (HR) relative to baseline observed in either dose groups or between R/R and TN populations. There was no evidence of PR interval prolongation above 240 msec. There were no treatment-related effects on QRS duration in any of the Treatment Groups. A total of 467 ΔQTcF measurements were included in the analysis. The population mean of baseline QTcF values was 402.0 msec with a SD of 15.2 msec. A concentration-dependent effect of ibrutinib on QTcF was not identified. Conclusions: Interim analyses of the data indicated that there was no evidence of clinically significant ECG findings or QTc prolongation with continuous daily dosing of ibrutinib at either the 420 mg or 840 mg dose in patients with TN or R/R CLL. Clinical trial information: NCT01105247.

Tigecycline does not prolong corrected QT intervals in healthy subjects.

We evaluated the effect of tigecycline (50-mg and 200-mg doses) on corrected QT (QTc) intervals and assessed safety and tolerability in a randomized, placebo-controlled, four-period crossover study of 48 (44 male) healthy volunteers aged 22 to 53 years. Fed subjects received tigecycline (50 mg or 200 mg) or placebo in a blinded fashion or an open-label oral dose of moxifloxacin (400 mg) after 1 liter of intravenous fluid. Serial electrocardiograms were recorded before, and for 96 h after, dosing. Blood samples for tigecycline pharmacokinetics were collected after each recording. QTc intervals were corrected using Fridericia's correction (QTcF). Pharmacokinetic parameters were calculated using noncompartmental methods with potential relationships examined using linear mixed-effects modeling. Adverse events were recorded. The upper limits of the 90% confidence interval for the mean difference between both tigecycline doses and placebo for all time-matched QTcF interval changes from baseline were <5 ms. The tigecycline concentrations initially declined rapidly and then more slowly. In the group given 50 mg of tigecycline, the pharmacokinetic parameters and means were as follows: maximum concentration of drug in serum (C(max)), 432 ng/ml; area under the concentration-time curve from time zero extrapolated to infinity (AUC0-∞), 2,366 ng · h/ml; clearance (CL), 21.1 liters/h; volume of distribution at steady state (V(ss)), 610 liters; and terminal half-life (t(1/2)), 22.1 h. Proportional or similar values were found for the group given 200 mg of tigecycline. Linear mixed-effects modeling failed to show an effect on QTcF values by tigecycline concentrations (P = 0.755). Tigecycline does not prolong the QTc interval in healthy subjects. This study has been registered at ClinicalTrials.gov under registration no. NCT01287793.

Effects of Bilastine on T-wave Morphology and the QTc Interval

The International Conference of Harmonisation (ICH) E14 guideline for thorough QT studies requires assessing the propensity of new non-antiarrhythmic drugs to affect cardiac repolarization. The present study investigates whether a composite ECG measure of T-wave morphology (Morphology Combination Score [MCS]) can be used together with the heart rate corrected QT interval (QTc) in a fully ICH E14-compliant thorough QT study to exclude clinically relevant repolarization effects of bilastine, a novel antihistamine. Thirty participants in this crossover study were randomly assigned to receive placebo, moxifloxacin 400 mg, bilastine at therapeutic and supratherapeutic doses (20 and 100 mg) and bilastine 20 mg co-administered with ketoconazole 400 mg. Resting ECGs recorded at 12 nominal time points before and after treatments were used to determine Fridericia corrected QTc (QTcF) and MCS from the T-wave characteristics: asymmetry, flatness and notching. There were no effects of bilastine monotherapy (20 and 100 mg) on MCS or QTcF at those study times where the bilastine plasma concentrations were highest. MCS changes for bilastine monotherapy did not exceed the normal intrasubject variance of T-wave shapes for triplicate ECG recordings. Maximum QTcF prolongation for bilastine monotherapy was 5 ms or less: 3.8 ms (90% CI 0.3, 7.3 ms) for bilastine 20 mg and 5.0 ms (90% CI 2.0, 8.0 ms) for bilastine 100 mg. There were no indications of bilastine inducing larger repolarization effects on T-wave morphology as compared with the QTcF interval, as evidenced by the similarity of z-score equivalents for placebo-corrected changes in MCS and QTcF values. This study shows that bilastine, at therapeutic and supratherapeutic dosages, does not induce any effects on T-wave morphology or QTcF. These results confirm the absence of an effect for bilastine on cardiac repolarization.

Romidepsin in the Treatment of Patients with Relapsed or Refractory Cutaneous T-Cell Lymphoma (CTCL): The New York University Cancer Center Experience

Abstract 4961 Background:Romidepsin, a histone deacetylase (HDAC) inhibitor has demonstrated overall response rates in CTCL of 35% in 2 separate phase 2 studies [enrolling 71 patients (pts) at 8 centers and enrolling 96 pts at 33 institutions worldwide] and is approved by the United States FDA for the treatment of CTCL in patients with progressive, persistent, or recurrent disease on or following at least 1 prior systemic therapy. Reports of clinical efficacy and toxicity outside the context of clinical trial are absent. Here, we report the largest single center experience of romidepsin in the treatment of relapsed or refractory CTCL following approval of the drug. Methods:Between June 2010 and June 2011, 11 pts with Mycosis Fungoides (MF) and Sezary syndrome (SS), the two predominant subtypes of CTCL, who had adequate organ function, ECOG PS 0 or 1 and who had failed 1 prior systemic therapy, were treated with single agent, romidepsin. Patients received romidepsin at a dose of 14 mg/m2 on days 1, 8, and 15 every 28 days. Response was measured with a quantitative composite which included skin involvement [severity-weighted assessment tool (SWAT) or erythroderma scale], lymph node involvement (CT or MRI scans), and blood involvement (circulating Sézary cells assessed by flow cytometry). Pruritus in pts with CTCL was assessed using a 10-point scale; relief defined as reduction of pruritus score of 3 points in pts with baseline score 3. ECGs were obtained (pre-/post-infusion on all treatment days in cycle 1, and on day 1 of subsequent cycles) to evaluate for potential cardiac toxicity. Serum Mg, Ca and K levels were measured with each treatment and supplementation given as necessary. Results:Ten pts (5 men and 5 women) with MF (Stages IB-IVA, 6 pts had advanced stage disease i.e ≥IIB) and 1 pt with SS with median age of 73 (59-77), median number of prior therapies 3 (1-8) were treated with a median of 4 cycles (1-12) of romidepsin. Nine pts received at least 2 cycles of therapy. Overall response rate (ORR) [CR (complete response) plus PR (partial response)] was 70% by composite assessment in the 10 assessable pts including 4 CR’s and 3 PR’s with 3 pts demonstrating disease progression. Treatment in 1 pt was discontinued due to concern for cardiovascular toxicity that was probably not treatment related. For these 10 pts, the median duration of response was 32 weeks (20-46) with ongoing responses in 4 of them (20-44 weeks).Of the 7 responders, 4 continue to maintain their response despite discontinuation of the drug with a mean of 21 weeks (4-42), 2 pts relapsed within 8 weeks of discontinuation of treatment and were retreated with romidepsin with subsequent achievement of similar response as with initial treatment and 1 pt continues to receive treatment. Three of the 7 responders, had received prior treatment with other HDAC inhibitors including vorinostat, panobinostat and belinostat. All 7 responders had prutitus relief. Median time to response was 6 weeks (3.5-8) and median time to progression was 38 weeks (27-42).The most frequent drug-related adverse events (AEs) (all grades, all cycles) were generally mild and included: nausea (50%; none with grade 3), fatigue (50%; none with grade 3) and decreased platelets (40%; none with grade 3). On review of 166 ECGs performed on the 11 pts, small clinically insignificant prolonged QT interval and corrected prolonged QTc interval was observed in only 1 pt. No pts had QTcF values>480 milliseconds and there was no change from baseline of > 20 milliseconds. The ECG values were not associated with functional cardiovascular changes or symptoms and did not lead to discontinuation of drug in any patient. Conclusion:In our single-center experience, romidepsin has greater ORR (70%, including 40% CR and 30% PR) than what has been reported in the phase II studies (ORR of 35%, including 6% CR and 28% PR) with comparable patient populations. Drug-related AEs were generally mild and consisted of GI disturbances and thrombocytopenia none of which were ≥ grade 3 compared to the 12% grade 3 and 4 toxicity observed in the phase 2 studies. We noted no clinically significant cardiovascular AEs in our pts in contrast with the previous phase 2 trials. Our experience also suggests that resistance to one HDAC inhibitor should not preclude treatment with romidepsin in CTCL pts. Disclosures:No relevant conflicts of interest to declare.

Abstract B193: Analysis of the concentration-QTc relationship for eribulin mesylate.

Abstract Introduction: Characterization of cardiac safety liability has become a critical part of clinical development plans for investigational drugs. For oncologic compounds, the standard “thorough QTc” study, which is typically conducted in healthy volunteers and includes placebo and a supratherapeutic dose, may not be possible due to drug toxicity. In the development of eribulin, a Phase 1 study was conducted to assess the potential effect of eribulin mesylate for QTc interval prolongation in female and male patients with recurrent and/or metastatic cancer. Results for two objectives are reported herein: to identify the more appropriate method of adjusting the QT interval for differences in heart rate (HR) and to develop an exposure-response model to characterize the relationship, if any, of time-matched change from baseline in QTc with exposure to eribulin. Methods: Subjects were administered 1.4 mg/m2 of eribulin mesylate on Days 1 and 8 of a 21-day Study Phase. The dataset for the PK/PD analysis consisted of measured drug concentrations and QTcF values from triplicate 12-lead ECGs extracted from the continuous Holter. The timepoints in the study used in the PK/PD analysis were pre-dose, after eribulin infusion, and 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, 6, 10, 24, and 48 hours after the start of eribulin administration on Cycle 1 Days 1 and 8, with time-matched points for baseline from Day 0. In the correction of QT interval for HR, the Fridericia method (QTcF=QT/(RR)0.33) was compared to an individually-derived method, QTcNi (QTcNi = QT + bi*(1000-RR), where RR is 60/(HR) and bi subject-specific slope). The performance of each correction algorithm was assessed via linear regression of individual subjects' QTc versus RR intervals at on-treatment visits. The HR correction method with the mean of squared slopes closer to zero was preferred. The concentration-QTc relationship was assessed using a linear mixed effects analysis of the relationship between baseline-adjusted QTcF interval (QTcF) and observed eribulin mesylate concentration, according to the equation: QTcF = α + β* [eribulin], where interindividual variability was estimated for both intercept () and slope (). The effect of treatment period (i.e., Day 1 or Day 8) on slope and intercept was also evaluated. Consideration was also given to nonlinear relationships. Results: Both QTcF and QTcNi corrected for HR reasonably well, with QTcNi providing a correction that was less dependent on HR. The means of squared slopes for QTcF were 0.0097 and 0.0083 on Day 1 and Day 8, respectively, while corresponding means for QTcNi were 0.0053 and 0.0069. Development of mixed-effects models for both QTcF and QTcNi indicated no relationship with eribulin concentrations. The observed difference in typical QTc between Day 1 and Day 8, estimated as 5.7 msec for QTcNi and 7.6 msec for QTcF, was modeled with a fixed effect on the intercept. Within-subject residual deviation was modeled additively, with zero mean and estimated standard deviation of 13 msec. Conclusion: QTcNi was more effective than QTcF in removing the HR dependence of corrected QT values. No relationship was found between eribulin concentration and QTc. No QTc prolongation was observed on Day 1, whereas QTc values on Day 8 were small (9 msec) and independent of eribulin plasma concentration. A QTc interval increase of this magnitude is not expected to be of clinical concern in this subject population. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B193.

Lack of an Effect of Standard and Supratherapeutic Doses of Linezolid on QTc Interval Prolongation

A double-blind, placebo-controlled, four-way crossover study was conducted in 40 subjects to assess the effect of linezolid on corrected QT (QTc) interval prolongation. Time-matched, placebo-corrected QT intervals were determined predose and at 0.5, 1 (end of infusion), 2, 4, 8, 12, and 24 h after intravenous dosing of linezolid 600 and 1,200 mg. Oral moxifloxacin at 400 mg was used as an active control. The pharmacokinetic profile of linezolid was also evaluated. At each time point, the upper bound of the 90% confidence interval (CI) for placebo-corrected QTcF values (i.e., QTc values adjusted for ventricular rate using the correction methods of Fridericia) for linezolid 600 and 1,200-mg doses were <10 ms, which indicates an absence of clinically significant QTc prolongation. At 2 and 4 h after the moxifloxacin dose, corresponding to the population T(max), the lower bound of the two-sided 90% CI for QTcF when comparing moxifloxacin to placebo was >5 ms, indicating that the study was adequately sensitive to assess QTc prolongation. The pharmacokinetic profile of linezolid at 600 mg was consistent with previous observations. Systemic exposure to linezolid increased in a slightly more than dose-proportional manner at supratherapeutic doses, but the degree of nonlinearity was small. At a supratherapeutic single dose of 1,200 mg of linezolid, no treatment-related increase in adverse events was seen compared to 600 mg of linezolid, and no clinically meaningful effects on vital signs and safety laboratory evaluations were noted.

To assess the effect of ridaforolimus on the QTc interval in patients with advanced cancer.

e13088 Background: Ridaforolimus (RIDA) (AP23573; MK-8669), a unique rapamycin analog and potent inhibitor of mTOR signaling, is being developed for treatment of solid tumors. We aimed to assess the effect of a single supratherapeutic dose of 100 mg RIDA on the QTc interval in advanced cancer patients. This dose was used to achieve an exposure similar to that following the clinical dose regimen. Methods: This was a partially blind, placebo-controlled, 2-part study of RIDA in advanced cancer patients. In Part 1, 2 days of ECG were performed for QTc assessment in a fixed sequence. On Day 1, patients received a single oral dose of placebo; on Day 2 they received a single oral dose of RIDA 100 mg. Each dose was followed by 24 h of Holter ECG. Blood samples for RIDA were measured at pre- and up to 24 h postdose on Day 2. In Part 2, patients had continued access to RIDA for potential clinical benefit, with only safety data collected. Results: 23 patients (8 males; 15 females) were enrolled. For Day 1 placebo treatment, 22 patients were included in the QTcF data; for Day 2 RIDA treatment, 20 were included in the QTcF data and 21 in the pharmacokinetic data. RIDA 100 mg did not prolong the QTcF interval. Upper bound of the 90% CI of the placebo-adjusted mean QTcF interval change-from-baseline was <10 ms at every time point through 24 h. The largest placebo-corrected RIDA change from baseline QTcF occurred at 10 h postdose, mean difference 3.89 ms, 90% CI (0.60, 7.17). After placebo or 100 mg RIDA administration, only 1 patient had QTcF values >450 ms (on both placebo and RIDA) and none had values >480 ms. Neither placebo nor treatment patients had a QTcF change-from-baseline >30 ms. Exposures after single dose RIDA 100 mg were a geometric mean whole blood AUC0-24 of 1875 h·ng/mL and Cmax of 186 ng/mL, approximating steady state exposure with the clinical dose regimen of 40 mg po QD x 5 consecutive days/week. However, these values do not achieve supratherapeutic exposure. RIDA was generally well tolerated, with no patients discontinued from Part 1 due to drug-related AEs. Conclusions: A single dose of RIDA (100 mg) does not prolong the QTc interval in advanced cancer patients and achieved exposures that approximated steady state exposures at the maximally tolerated clinical dose and regimen.

Comparison of 5 methods of QT interval measurements on electrocardiograms from a thorough QT/QTc study: effect on assay sensitivity and categorical outliers

We studied moxifloxacin-induced QT prolongation and proportion of categorical QTc outliers when 5 methods of QT measurement were used to analyze electrocardiograms (ECGs) from a thorough QT study. QT interval was measured by the threshold, tangent, superimposed median beat, automated global median beat, and longest QT methods in a central ECG laboratory in 2730 digital ECGs from 39 subjects during placebo and moxifloxacin treatment. All 5 methods were able to demonstrate statistically significant moxifloxacin-induced QTcF prolongation. However, lower bound of 95% 1-sided confidence interval of QTcF prolongation did not exceed 5 milliseconds with the longest QT method. More QTcF outliers were observed with the longest QT and tangent methods, whereas the other 3 methods were comparable. QTcF values greater than 500 milliseconds were observed only with moxifloxacin by the tangent method, and with moxifloxacin and placebo by the longest QT method. The method of QT measurement must be considered when interpreting individual thorough QT/QTc studies.

Effect of artesunate and mefloquine in combination on the Fridericia corrected QT intervals in Plasmodium falciparum infected adults from Thailand

To ascertain whether mefloquine (MQ) produces electrocardiogram (ECG) changes that could be a risk for Torsades de Pointe (TdP), a potentially malignant, ventricular tachyarrhythmia. We measured the Fridericia corrected QT (QTcF) intervals on 12 lead ECGs on days (D) 0, 3, 7 in Plasmodium falciparum infected adults, treated with oral artesunate (AS) and MQ as a new fixed dose (n = 25) combination or loose tablets (n = 25) over 3 days. Target total doses were 12 mg/kg of AS and 24-25 mg/kg of MQ. MQ concentrations ([MQ]) were measured by HPLC. All ECG intervals were similar between drug arms and were combined for analysis. Mean QTcF values were 389 (D0), 407 (D3) and 399 (D7) ms (Ps < 0.003 vs. D0); corresponding heart rates and [MQ]s were 83, 67 and 73 beats/minute (Ps ≤ 0.0003 vs. D0) and 0, 3095 and 1721 ng/ml. One male patient (loose arm) had a D3 QTcF 504 ms (D0 406 ms, D7 433 ms). In the modelling of QTcF and JTcF from D0 to D7, significant effects were observed individually for [MQ], temperature and heart rate (HR). The MQ AUC(0-∞) was not a significant factor. Using a manual descending, model building approach to select variables, the HR was the only significant variable (P = 0.001) over time in the model that best explained the changes in the QTcF and JTcF intervals. In this small group of patients, slowing heart rates due to malaria resolution best explained the observed increases in the QTcF intervals.

Substitution of (R,S)-Methadone by (R)-Methadone

Methadone is administered as a chiral mixture of (R,S)-methadone. The opioid effect is mainly mediated by (R)-methadone, whereas (S)-methadone blocks the human ether-à-go-go-related gene (hERG) voltage-gated potassium channel more potently, which can cause drug-induced long QT syndrome, leading to potentially lethal ventricular tachyarrhythmias. To investigate whether substitution of (R,S)-methadone by (R)-methadone could reduce the corrected QT (QTc) interval, (R,S)-methadone was replaced by (R)-methadone (half-dose) in 39 opioid-dependent patients receiving maintenance treatment for 14 days. (R)-methadone was then replaced by the initial dose of (R,S)-methadone for 14 days (n = 29). Trough (R)-methadone and (S)-methadone plasma levels and electrocardiogram measurements were taken. The Fridericia-corrected QT (QTcF) interval decreased when (R,S)-methadone was replaced by a half-dose of (R)-methadone; the median (interquartile range [IQR]) values were 423 (398-440) milliseconds (ms) and 412 (395-431) ms (P = .06) at days 0 and 14, respectively. Using a univariate mixed-effect linear model, the QTcF value decreased by a mean of -3.9 ms (95% confidence interval [CI], -7.7 to -0.2) per week (P = .04). The QTcF value increased when (R)-methadone was replaced by the initial dose of (R,S)-methadone for 14 days; median (IQR) values were 424 (398-436) ms and 424 (412-443) ms (P = .01) at days 14 and 28, respectively. The univariate model showed that the QTcF value increased by a mean of 4.7 ms (95% CI, 1.3-8.1) per week (P = .006). Substitution of (R,S)-methadone by (R)-methadone reduces the QTc interval value. A safer cardiac profile of (R)-methadone is in agreement with previous in vitro and pharmacogenetic studies. If the present results are confirmed by larger studies, (R)-methadone should be prescribed instead of (R,S)-methadone to reduce the risk of cardiac toxic effects and sudden death.

QT Interval Measurements in Patients with Hematologic Malignancies and Solid Tumors Treated with Oral Panobinostat (LBH589).

Abstract 3781Poster Board III-717 IntroductionPanobinostat (LBH589), a hydroxamic acid derivative, is a potent pan-deacetylase inhibitor (DACi) with broad anti-tumor activity in preclinical models and promising clinical activity in Phase I/II studies. Prolongation of the QT interval has been reported with DACis, and data on file indicate this is a class effect associated with inhibition of maturation of hERG – a component of potassium ion channels. This analysis represents the first extended evaluation of the incidence of QT prolongation in patients treated with oral, single-agent panobinostat at different doses and schedules. Patients and methodsAn analysis was performed on pooled data from eight completed or ongoing Phase I and II studies of single-agent oral panobinostat in patients with advanced hematologic malignancies or solid tumors. The following doses and 28-day cycle dosing schedules were analyzed: doses of 20 to 60 mg/dose administered TIW (Days 1, 3 and 5) weekly (QW), or doses of 30 to 60 mg/dose administered TIW every other week (QOW). Twelve-lead electrocardiograms (ECGs) were performed in triplicate pre- and 3 hours post-dose on Days 1, 5 and 26 in Cycle 1, and as a single reading pre-dose on Days 8 and 15. In subsequent cycles, a single ECG was performed on Day 1 pre-dose. All ECGs were evaluated centrally. QT intervals were corrected individually for heart rate using Fridericia's formula and were reported as absolute QTcF and mean QTcF change from baseline. In addition, a mixed effect model was used to explore the relationships between QTcF change and baseline characteristics within the pooled data of oral, single-agent panobinostat with two schedules – QW and QOW. ResultsAnalysis of oral TIW QW dosing is available based on ECGs from 392 patients (241 female/151 male), with a median age of 60 years (range: 16–88), receiving oral panobinostat at 20 mg/dose (n=282), 30 mg/dose (n=22), 40 mg/dose (n=34), or 60 mg/dose (n=54). At panobinostat doses of ≤40 mg/dose, QTcF >500 ms and mean QTcF change from baseline >60 ms on at least one ECG were reported in <1% and 3.5% of patients, respectively. Across these dose levels, 30–50% of patients experienced a clinically non-significant QTcF change of 30 to 60 ms from baseline. At the 60 mg dose level, QTcF >500 ms and mean QTcF change from baseline >60 ms were reported in 5.6% and 9.3% of patients, respectively. Most QT prolongation events occurred in a single ECG and were not persistent over time. No cases of Torsade de pointes were observed with oral panobinostat. A separate analysis of QTcF change from baseline across two schedules was performed on 436 treated patients (178 female/258 male), with a median age of 58 years (range: 16–88), receiving oral panobinostat (20, 30 or 40 mg/dose TIW QW [n=384], and 30 or 60 mg/dose TIW QOW [n=52]). This analysis showed that the greatest mean QTcF changes from baseline were observed on Days 1 and 5 of Cycle 1. Later in the cycle, a trend was noted of QTcF values to return to baseline, with QW dosing. ConclusionsAbsolute QTcF prolongation >500 ms and changes >60 ms from baseline were infrequently reported with weekly administration of oral panobinostat up to 40 mg/dose TIW. These data support a significant reduction of the ECG monitoring schedule in future studies investigating oral panobinostat at doses up to 40 mg/dose on a TIW schedule. ECG monitoring based on the original schedule is ongoing in a clinical trial investigating the oral dose of 60 mg/dose TIW at QW schedule in patients with refractory AML to better characterize the QTcF interval at this dose level. Disclosures:Weber:Novartis Pharma AG: Employment. Tai:Novartis: Employment. Paul:Novartis: Employment. Schindler:Novartis: Employment. Woo:Novartis: Employment. Spence:Novartis: Employment. Marlowe:Novartis: Employment. Lin:Novartis: Employment.

A Single Supratherapeutic Dose of Vorinostat Does Not Prolong the QTc Interval in Patients with Advanced Cancer

This dedicated QTc phase I study, conducted in advanced-stage cancer patients, assessed the effect of a single supratherapeutic dose (800 mg) of vorinostat on the QTc interval. A randomized, partially blind, placebo-controlled, two-period, crossover study was conducted. Patients (n = 25) received single doses of 800 mg vorinostat and placebo in the fasted state. Holter electrocardiogram monitoring was done before each treatment and for 24 h postdose. Blood samples for vorinostat concentration were collected through 24 h postdose following vorinostat treatment only. Prescribed electrocardiogram and blood sampling times were designed to capture the expected C(max) of vorinostat. Twenty-four of the 25 patients enrolled in the study were included in the QTc analysis. The upper bound of the two-sided 90% confidence interval for the QTcF interval for the placebo-adjusted mean change from baseline of vorinostat was <10 ms at every time point. No patient had a QTcF change from baseline value >30 ms. One patient had QTcF values >450 ms (seen after both vorinostat and placebo administration) and none had values >480 ms. Mean AUC(0-infinity) and C(max) values attained were on the order of approximately 1.93- and approximately 1.41-fold higher, respectively, compared with the 400 mg clinical dose. Based on assessment of clinical and laboratory adverse experiences, single doses of 800 mg vorinostat were generally well tolerated. Administration of a single supratherapeutic dose of the histone deacetylase inhibitor vorinostat is not associated with prolongation of the QTc interval. A dedicated QTc study in advanced cancer patients is a robust means for assessing risk for ventricular repolarization prolongation.

A phase II study of a 1-hour infusion of romidepsin combined with bortezomib for multiple myeloma (MM) patients with relapsed or refractory disease

e19508 Background: Nonclinical studies have demonstrated that histone deacetylase inhibitors (HDACi) significantly reduce the growth of MM cells and enhance cytotoxicity of the proteasome inhibitor bortezomib (Velcade). Romidepsin, a pan-HDACi, has previously shown activity for patients (pts) with relapsed or refractory MM when administered as a 4-hr infusion in combination with dexamethasone and bortezomib. Methods: This open-label, multi-center, phase II study (GPI-08–0006) was initiated to evaluate the activity and safety of a 1-hr infusion of romidepsin in combination with bortezomib for MM pts with relapsed or refractory disease and to evaluate the safety and single dose pharmacokinetics (PK)/pharmacodynamics of romidepsin in the first 5 pts. Pts received 10 mg/m2 romidepsin on days 1, 8 and 15 and 1.0 mg/m2 bortezomib on days 1, 4, 8 and 11 of a 28-day cycle. PK sampling and triplicate ECGs were performed at 0, 0.25, 0.5, 1, 2, 3, 4, 6 and 24 hrs after initiation of the first 1-hr infusion of romidepsin. Results: To date, 5 pts have been enrolled (median age 68 [range, 65–72]) 2 pts who relapsed from recent bortezomib-containing regimens experienced minimal responses after 2 cycles. 2 pts have experienced grade 3 thrombocytopenia. No pt had a QTcF value of &gt;480 ms the mean change in QTcF from baseline to Cmax was 4.2 ms (-10 to 13). Values for PK parameters are included in the table . When compared with data from pts who were treated with a 4-hr infusion of 14 mg/m2, the Cmax of the 1-hr infusion of romidepsin 10 mg/m2 was ∼ 20% higher and exposure (AUC0–24hr) was reduced by 70%. Conclusions: Preliminary data suggest that the 1-hr infusion of romidepsin combined with bortezomib is active for pts with MM relapsed or refractory to bortezomib. Based on the initial incidence of grade 3 thrombocytopenia and PK data, additional pts are being treated on the same schedule but with a reduced dose of romidepsin (8 mg/m2). This study continues to enroll pts. [Table: see text] [Table: see text]

Clinically Significant Responses Achieved with Romidepsin in Treatment-Refractory Cutaneous T-Cell Lymphoma: Final Results from a Phase 2B, International, Multicenter, Registration Study

Background: Responses to romidepsin, a novel pan-HDAC inhibitor, have been observed in patients (pts) with cutaneous T-cell Lymphoma (CTCL). This Phase 2B, singlearm, open-label registration study enrolled pts with CTCL (Stages IB–IVA) at 33 European and US sites. Pts with histologically confirmed CTCL who failed ≥1 prior systemic therapy, had adequate organ function, and ECOG PS 0 or 1 were eligible. Exclusions included significant cardiovascular abnormality or treatment with QTc-prolonging or CYP3A4-inhibiting drugs. Pts received romidepsin 14 mg/m2 as a 4-hr IV infusion on days 1, 8, and 15 every 28 days for up to 6 cycles (extended for stable disease or response).Aim: The primary endpoint was the response rate among evaluable pts, measured by a combination of a weighted scoring instrument to determine skin involvement (SWAT), imaging, and circulating Sézary cells (as applicable).Results: 96 pts were enrolled and received romidepsin (as-treated); 72 (75%) were evaluable (≥2 cycles) for efficacy. Enrollment is complete, 4 pts with confirmed PR continue to receive romidepsin on extended treatment, 5 pts off-treatment are being followed. Mean age of all pts was 57±12 yrs, and median time since diagnosis was 3 yrs (range <1–26). 68 pts (71%) had disease stage ≥IIB. Median number of prior systemic therapies was 2 (range 1–8). Response (assessed by investigators) and pruritus relief (assessed by visual analog scale [VAS]) data are in the table. Objective disease response rate (ORR) was not lower in pts with advanced-stage disease; 23 (47.9%) of 48 pts with stage IIB-IVA and 7 (29%) of 24 pts with stage IB-IIA achieved OR. With a median follow-up of 5.3 months (mo), median duration of response has not been reached. 50% of responders (evaluable pts) have maintained a response for ≥5 mo and 30% for ≥8 mo. The maximum duration of response was 19.8 mo. 24 (80%) of the 30 pts with a response had not progressed as of the last assessment. Most pts (48/52; 92%) with pruritus at baseline (≥30 mm on VAS) had some relief, including most of those with severe pruritus. Adverse events (AEs) occurred in 93 pts (97%). AEs reported in ≥20% of pts were nausea (56%), asthenia (52%), vomiting (29%), anorexia (23%), hypomagnesemia (21%), and pyrexia (20%). AEs ≥ grade 3 occurred in 32 pts (33%), most commonly fatigue (7%), disease progression (4%), and pyrexia (4%). 21 pts (22%) had a serious AE; the most frequently reported serious AEs were disease progression (6%), pyrexia (3%), sepsis (2%), tumor lysis syndrome (2%), and hypotension (2%). 20 pts (21%) withdrew because of AEs, including fatigue (4%), pyrexia (2%), prolonged QT (2%), and CTCL progression (2%). 6 pts (6%) died, 1 possibly related to treatment. Mean QTcF change from baseline to 2 hrs post-dose was 4.6 msec using baseline assessments before any anti-emetics and 1.3 msec using baseline assessment after anti-emetics. No pts had QTcF values >500 msec.Conclusions: This study shows clinical benefit associated with romidepsin use in treatment-refractory CTCL, with pts achieving durable response and relief from pruritus. Toxicities associated with romidepsin were tolerable and manageable.Evaluable Pts N=72As-treated Pts N=96Confirmed ORR42%34%PR, n (%)24 (33%)27 (28%)CCR, n (%)6 (8%)6 (6%)SD90a, n (%)26 (36%)28 (29%)Overall disease control (CCR+PR+SD90)56 (78%)61 (64%)Median time (mo) to response (range)1.9 (0.9–4.8)1.9 (0.9–4.8)Median time (mo) to disease progression (range)9.0 (2.7–21.7)8.3 (0–21.7)Confirmed OR in stage ≥ IIB, n (%)23/48 (48%)26/68 (38%)Relief of pruritusb, n (%)25/52 (48%)NARelief of severe pruritus, n (%)16/29 (55%)NAa stable disease for ≥90 daysb relief = ≥ 30mm decrease on 100mm VAS or score of 0 for 2 consecutive cycles

A Phase II Study of Oral Panobinostat (LBH589) in Adult Patients with Advanced Refractory Multiple Myeloma

Panobinostat (LBH589) is a highly potent pan-deacetylase inhibitor (DACi), which induces cytotoxicity at <10nM in multiple myeloma (MM) cell lines resistant to conventional therapies. It modulates 2 targets implicated in MM by controlling cell proliferation and survival through HSP90 and inducing apoptosis through the aggresome pathway. Here we report the preliminary results of a Phase II, single arm, multicenter study of panobinostat in patients with measurable MM disease who had received at least 2 prior lines of therapy (including bortezomib and lenalidomide or thalidomide) and who were also refractory to their most recent line of therapy. The study was designed to assess: response rate (CR/PR) by the IBMTR/EBMTR criteria, safety, and tolerability of 20 mg/day of oral panobinostat given on a Monday/Wednesday/Friday (MWF) dosing schedule. 3 or more responders in 25 patients in stage 1 of the study were required for the initiation of Stage 2. A total of 38 pts (24 males, 14 females; median age 61 years [43–72]) have been enrolled between February and October 2007. Median time since last prior therapy was 33 days, median number of prior therapies was 5 (2–12). Median treatment duration was 45 days (5–377 days). Overall, panobinostat was well tolerated, and no new safety signals were reported. Mild or moderate level of nausea, as well as fatigue/asthenia, occurred in half of the patients. The most common Grade 3/4 AEs were cytopenias, with neutropenia, thrombocytopenia, and anemia in 32%, 26%, and 16% of patients, respectively. Other Grade 3/4 AEs included infections: 8 occurrences (3 of pneumonia; 2 of septic shock; and back pain, hypercalcemia, and hypokalemia in 3 pts each). No cardiac (including significant QTc prolongation, pericarditis, or pericardial effusion) or thromboembolic events were reported. SAEs potentially related to study drug were observed in 3 pts and included nausea (2), diarrhea and vomiting (1), and reduced general condition (1). 5 patients discontinued therapy for AE: 2 due to acute renal failure which was progression coincident, 2 due to elevated creatinine suspected to be study drug related, and 1 for worsening on study of peripheral neuropathy (non-related). 1 patient died on study due to a cerebral vascular accident (assessed by the investigator as not study drug related). QT intervals (QTcF) were monitored per study protocol and out of >1500 post dose ECGs, 1 pt showed a Grade 2 prolongation of QTcF value above 480 ms, 2 pts had a QTcF increase of ≥60 ms compared to baseline, and 10 pts had a minimal 30–<60 ms increase of QTcF compared to baseline. A clinical durable response was observed in a 43-yr-old female patient, whose urine kappa light chain MM with bone lesions was progressing on lenalidomide/dexamethasone prior to enrollment. The patient had 5 prior lines of therapy, including auto-SCT twice (5 years apart), bortezomib, and thalidomide. Response was rapid, with a 60% reduction of urine M protein at Cycle 2 and 90% at Cycle 4. PR was confirmed in Cycle 7, including stabilized bone lesions, and is sustained at 11 months on therapy with urine light chain stable below the “measurable disease” level of 100mg/24hrs and urine IF still positive, thus a VGPR. A quick and dramatic reduction in angiogenesis markers (VEGF, sVEGFR1, and bFGF) was seen starting on Cycle 1, Day 8 of treatment, as well as a reduction (50%) of seric free light chain, which continued further throughout the later cycles. A second patient on study for >12 months is continuing to show clinical benefit after failing 10 prior lines of therapy (including Auto-SCT, bortezomib, lenalidomide, and thalidomide) and is maintaining MR. Stable disease observations of >3 months occurred in 3 pts. Single-agent, oral panobinostat at 20 mg/day thrice weekly was well tolerated and safe in this study. Evidence has since been obtained from clinical responses in patients with various hematological malignancies that higher doses of single-agent panobinostat can provide more optimal dosing schedules than the 20 mg dose. Thus, although the current study at the 20 mg schedule did not meet its objective, the observation of 1 durable VGPR and 1 durable and ongoing MR, in addition to transient disease stabilization in 3/38 patients, are encouraging results, especially at this low dose, warranting further clinical investigation of panobinostat. The analysis of final study results will be presented.

Raltegravir Thorough QT/QTc Study: A Single Supratherapeutic Dose of Raltegravir Does Not Prolong the QTcF Interval

Raltegravir is a novel HIV-1 integrase inhibitor with potent in vitro activity (IC(95) = 31 nM in 50% human serum). A double-blind, randomized, placebo-controlled, double-dummy, 3-period, single-dose crossover study was conducted; subjects received single oral doses of 1600 mg raltegravir, 400 mg moxifloxacin, and placebo. The upper limit of the 2-sided 90% confidence interval for the QTcF interval placebo-adjusted mean change from baseline of raltegravir was less than 10 ms at every time point. For the raltegravir and placebo groups, there were no QTcF values >450 ms or change from baseline values >30 ms. A mean C(max) of approximately 20 muM raltegravir was attained, approximately 4-fold higher than the C(max) at the clinical dose. Moxifloxacin demonstrated an increase in QTcF at the 2-, 3-, and 4-hour time points. Administration of a single supratherapeutic dose of raltegravir does not prolong the QTcF interval. A single supratherapeutic dose design may be appropriate for crossover thorough QTc studies.

Randomized, Double-Blind, Crossover Study to Investigate the Effect of Rivaroxaban on QT-Interval Prolongation

Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. Unwanted pro-arrhythmic effects are a common reason for drugs failing to gain regulatory approval; these properties can be detected by assessing the effect of the drug on the QT interval. This study was performed, in accordance with International Conference on Harmonisation (ICH) E14 guidance, to assess whether rivaroxaban prolongs the QT interval. This was a prospective, randomized, double-blind, double-dummy, four-way crossover study. The study was conducted at a clinical pharmacology research unit. Healthy male and female subjects (n = 54) aged > or =50 years were enrolled and remained in the study unit for 3 days for each treatment. Of these, 50 patients were eligible for the QT analysis. Subjects received single oral doses of rivaroxaban 45 mg or 15 mg, moxifloxacin 400 mg (positive control), or placebo. Multiple ECGs were taken at frequent intervals after drug administration, and the QT interval was measured manually under blinded conditions at a central laboratory. The Fridericia correction formula (QTcF) was used to correct the QT interval for heart rate. The primary outcome was the effect of rivaroxaban or moxifloxacin on the placebo-subtracted QTcF 3 hours after administration. The frequency of outlying QTcF values and the tolerability of the treatments were also assessed. All treatments were well tolerated and had no effect on heart rate. Moxifloxacin established the required assay sensitivity; placebo-subtracted QTcF 3 hours after moxifloxacin administration was prolonged by 9.77 ms (95% CI 7.39, 12.15). Placebo-subtracted QTcF values 3 hours after rivaroxaban administration were -0.91 ms (95% CI -3.33, 1.52) and -1.83 ms (95% CI -4.19, 0.54) with rivaroxaban 45 mg and 15 mg, respectively. QTcF was not prolonged with rivaroxaban at any time, and the frequency of outlying results with rivaroxaban and placebo was similar. This thorough QT study, which was performed in accordance with ICH E14 guidelines, shows that rivaroxaban does not prolong the QTc interval. Therefore, the potential of rivaroxaban for the prevention and treatment of thromboembolic disorders, including chronic cardiovascular disorders, can be investigated in appropriate clinical studies without the need for intensive monitoring of the QTc interval.