QT Prolongation andOncology Drug

Development Michael G. Fradley, MDa,*, Javid Moslehi, MDb,c,d

KEYWORDS

� QT prolongation � Cardiotoxicity � Cardio-oncology � Chemotherapy � Cancer treatment� Torsades de pointes

KEY POINTS

� Many pharmaceutical agents interact with cardiac ion channels resulting in prolongation of the QTinterval, which is associated with the development of torsades de pointes.

� QT interval monitoring is an essential part of pharmaceutical development and significant increasesin the QT interval may prevent a drug from gaining approval.

� Given that QT interval prolongation does not always translate into an increased clinical risk ofarrhythmia, current guidelines may be too restrictive for novel oncology drugs.

� New strategies should be considered for monitoring the QT interval and risk of abnormal ventricularrepolarization in anticancer pharmaceutical agents.

� Given the significant influx of novel oncology pharmaceutical agents with associated QT prolonga-tion, experience in both cardio-oncology and electrophysiology is necessary to provide appropriateclinical guidance.

INTRODUCTION

QT prolongation has been associated with thedevelopment of a dangerous and potentially life-threatening form of polymorphic ventricular tachy-cardia known as torsades de pointes (TdP).Despite this association, the QT interval hasbeen shown to be a poor predictor for the develop-ment of TdP. Unfortunately, there are few otherreadily available methods to better determine riskof TdP. Multiple factors have been implicated inQT interval prolongation, including electrolyteabnormalities or underlying genetic disorders.In addition, pharmaceutical agents have beenshown to prolong the QT interval and in rare

The authors have nothing to disclose.a Division of Cardiovascular Medicine, Morsani CollegeGeneral Circle, Tampa, FL 33606, USA; b Division of CVanderbilt-Ingram Cancer Center, Vanderbilt UniversityTN 37232, USA; c Division of Hematology-Oncology, Depter, Vanderbilt University School of Medicine, 2220 POncology Program, Vanderbilt University School of Med* Corresponding author.E-mail address: mfradley@health.usf.edu

Card Electrophysiol Clin - (2015) -–-http://dx.doi.org/10.1016/j.ccep.2015.03.0131877-9182/15/$ – see front matter � 2015 Elsevier Inc. All

circumstances lead to TdP. As a result, QT moni-toring has become an essential part of drug devel-opment. This issue has become particularly ofconcern given the explosion of novel targeted can-cer therapies in the last decade, which have revo-lutionized oncology treatment. Although it isessential to mitigate risk when developing novelpharmaceutical agents, cancer drugs represent aunique challenge as they are developed to treat alife-threatening condition for which there may notbe other treatment options. Given that QT intervalprolongation does not always translate intoincreased clinical risk of arrhythmia, current guide-lines may be too restrictive for novel oncologydrugs. In this review, the unique challenges of QT

of Medicine, University of South Florida, 2 Tampaardiovascular Medicine, Department of Medicine,School of Medicine, 2220 Pierce Avenue, Nashville,artment of Medicine, Vanderbilt-Ingram Cancer Cen-ierce Avenue, Nashville, TN 37232, USA; d Cardio-icine, 2220 Pierce Avenue, Nashville, TN 37232, USA

rights reserved. cardiacEP.th

eclinics.com

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interval monitoring in the development of cytotoxiconcology drugs are discussed and agents areidentified that may require more intensive evalua-tion when given to patients. It is also posited thatgiven the relative target specificity of some ofthese novel therapies, QT prolongation mayprovide insight into basic electrophysiology.

BASIC ELECTROPHYSIOLOGY OF THE QTINTERVAL AND TORSADES DE POINTES

On a surface electrocardiogram (ECG), the QT in-terval is measured from the beginning of the QRScomplex to the end of the T wave and representsthe entirety of ventricular depolarization and repo-larization (Fig. 1).1 At a cellular level, this electricalprocess, also known as the action potential, ismediated by channels in the myocardial cell mem-brane that regulate the flow of ions into and out ofthe cardiac cells (Fig. 2).2 Normal depolarization isdue to the rapid inflow of positively charged ions(sodium and calcium), whereas repolarization isdue to outflow of potassium ions. The action po-tential consists of 5 distinct phases. Phase 0 (de-polarization) occurs with the opening and closingof Na1 channels, represented by a sharp initial up-stroke. Phase 1 begins the repolarization processwith the rapid transient outflow of K1 ions. Phase2 (plateau phase) is the result of a balance be-tween inward Ca21 current and outward flowthrough K1 channels (particularly the slow delayedrectifier potassium channel IKs). During phase 3(rapid repolarization), the Ca21 channels closeand the K1 channels remain open. The channelpredominantly responsible for phase 3 is the rapid

Fig. 1. Surface electrocardiogram with QT interval represeraphy: a simplified approach. 7th edition. St. Louis (MO):

delayed rectifier potassium channel, IKr. Phase 4 isa return to baseline (resting membrane potential)when the cell is not being stimulated.3,4

Sustained inflow of Na1 ions or impaired outflowof K1 ions leads to delay in the action potential andthus QT interval prolongation. In the 1950s and1960s, genetic syndromes of QT prolongationwere first identified, most of which are due tomutations in these ion channels involved in thecardiac action potential.5,6 In addition, electrolyteabnormalities and specific drug effects can alsolead to QT prolongation. Most pharmaceuticalagents that prolong the QT interval do so byimpacting the function of the IKr channel, whichis encoded by the gene KCNH2. This gene isalso referred to as the human ether-a-go-gogene (HERG). This channel is known to interactwith a variety of structurally diverse compounds.4

Afterdepolarizations are abnormal oscillatorychanges in cell membrane voltage that disruptnormal repolarization. They are called early after-depolarizations (EAD) when they occur duringphase 2 or 3 of the action potential and delayedafterdepolarizations when they occur during phase4. EADs most frequently occur in the setting of abaseline prolonged action potential duration.7

The resulting myocardial electrical heterogeneityrenders it vulnerable to the development of TdP,typically occurring after a salvo of several EADs;this is manifested by long-short sequences onthe ECG.7,8 Although transmural dispersion ofrepolarization is a significantly better predictor forTdP compared with QT prolongation, it is noteasily measured, and the QT interval is a frequently

ntation. (From Goldberger AL. Clinical electrocardiog-CV Mosby; 2006; with permission.)

Fig. 2. Ventricular myocyte action potential curve with associated ion channels. APD, action potential duration;NCX, sodium-calcium exchanger. (From Nattel S, Carlsson L. Innovative approaches to anti-arrhythmic drug ther-apy. Nat Rev Drug Discov 2006;5:1034–49; with permission.)

QT Prolongation and Oncology Drug Development 3

used surrogate to determine risk.8,9 Certain cellpopulations within the heart, specifically thoseconstituting the Purkinje fibers and the midmyo-cardium (M cells), are particularly vulnerable tothis phenomenon.10,11

QT INTERVAL MEASUREMENTAND ANALYSIS

Accurate measurement of the QT interval can bechallenging (Box 1). One study revealed that lessthan 25% of cardiologists and only 62% of“arrhythmia experts” could accurately identify QTprolongation.12 When measuring the QT interval,the longest QT interval should be used (typicallyin the limb leads); however, if this measurementdiffers by more than 40 ms from other leads, itmay be erroneous and measurement from otherleads should be considered. It is recommended

Box 1Key points for accurate QT measurements

1. Measure longest QT interval

2. Average measurement over several beats

3. Use tangent method to determine the end of the

4. Avoid measuring U waves in most circumstances

5. During atrial fibrillation, average the QT interval m

6. Use the JT interval in patients with bundle branch

7. Always manually verify electronic QT measuremen

that this measurement should be averaged over3 to 5 beats. It can be particularly challenging todetermine the end of the T wave to appropriatelymeasure the QT interval. One recommendation isto draw a tangent from the steepest slop of thedescending end of the T wave to the isoelectricline, typically in lead II or V5 (Fig. 3).13 In addition,measurement of the QT interval should not includeU waves unless they clearly merge with the Twave. It is essential to manually validate the QTmeasurement recorded by an electronic ECGmachine because errors frequently occur.3,14,15

Atrial fibrillation and wide QRS complexes (dueto either conduction defects/bundle branch blocksor ventricular pacing) pose unique problems foraccurately assessing the corrected QT (QTc) inter-val. There is no consensus as to the correct way tomeasure and interpret QTc intervals in the setting

T wave

ore than 10 beats

blocks or ventricular pacing

ts

Fig. 3. QT interval measurement using the tangent method. (Adapted from Anttonen O, Junttila MJ, Rissanen H,et al. Prevalence and prognostic significance of short QT interval in a middle-aged Finnish population. Circulation2007;116(7):714–20; with permission.)

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of atrial fibrillation. Because of the variability of theR-wave intervals during atrial fibrillation, theQT interval can change in each beat. Some ex-perts recommend averaging QTc measurementsgreater than 10 beats; others suggest averagingthe QTc measurements associated with the short-est and longest R-R intervals.3,16 Similarly, there isno clear consensus for the measurement of theQTc in the setting of wide QRS complexes. Ex-perts recommend using the JT interval (QTc-QRSduration); however, this can be confusing andcumbersome especially for noncardiologists.14,17

It has been suggested to avoid initiation of adrug if the QTc interval is greater than 500 ms inthe setting of ventricular conduction delay.3

The QT interval is longer at slower heart ratesand shorter at faster heart rates. Several formulaehave been developed to adjust for this variation(Table 1). The Bazett formula, in which the QT in-terval is divided by the square root of the RR inter-val, is most frequently used in clinical practice;however, this method is inaccurate at slower andfaster heart rates.18 Other formulae include the

Table 1QT correction formulae

Bazett Fridericia

Mathematicalformula

QTc 5 QT/(RR1/2) QTc 5 QT/(RR1/3)

Type Nonlinear Nonlinear

Advantages Simple; mostwidely used inpractice

More accurate atslower HR (risk ofTdP is greater atslower HR)

Disadvantages Overcorrects atfast HRs andundercorrectsat slow HRs

Overcorrects at high

Abbreviations: HR, heart rate; QT, QT interval; QTc, QT correctAdapted from Curigliano G, Spitaleri G, Fingert HJ, et al. Dru

an efficient and safe anticancer drug development. Eur J Canc

Fridericia formula (QT interval divided by thecubed root of the RR interval) and the FraminghamLinear Regression Equation. The Framinghamequation is supported by empiric epidemiologicdata and may be a more accurate approachwhen evaluating large populations. The Bazettand Fridericia formulas are based onmathematicalmodeling/reasoning and are most often used fordrug development monitoring. Unfortunately,none of these methods have been evaluated andcompared with one another to determine whichis most accurate at predicting risk of TdP.14,19

RISK FACTORS FOR CORRECTED QTPROLONGATION AND TORSADES DE POINTES

Multiple pharmaceutical agents are known to pro-long the QT interval, typically by inhibiting ormodulating the function of the HERG channel.Nevertheless, most episodes of drug-inducedTdP occur in the setting of other patient-specificor acquired risk factors. For example, genetic con-ditions (long QT syndrome [LQTS]) have been

Framingham Hodges

QTc 5 QT 1 0.154(1000 � RR)

QTc 5 QT 1 1.75(HR-60)

Linear Linear

Adaptable acrossgenders;population-based formula

Useful with multiplepopulations

HRs Uncertain validity inpopulations otherthan FraminghamHeart Study;overcorrects athigh HRs

Less correlationwith HR variability;overcorrects athigh HRs

ion; RR, RR interval.g-induced QTc interval prolongation: a proposal towardser 2008;44(4):494–500.

QT Prolongation and Oncology Drug Development 5

identified that phenotypically present with QT pro-longation and an increased risk of sudden cardiacdeath, typically due to mutations that affect theions channels responsible for the action potential.Most forms are due to either a reduction in the out-ward potassium currents (LQTS-1: IKs; LQTS-2:IKr) or an enhancement of the inward sodium cur-rent (LQTS-3: INa). Other forms of LQTS are due toabnormalities in proteins that affect ion channeltrafficking or function. When these patients aretreated with certain drugs, the additive QT pro-longing effect can be substantial.20,21

Nonpharmacologic factors can also impact theQT interval (Box 2). Electrolyte abnormalities(hypokalemia or hypomagnesemia), bradycardia,left ventricular hypertrophy and congestive heartfailure, intracranial pathologic abnormality, HIVinfection, connective tissue disorders, and hypo-thermia are also all known to prolong the QT inter-val.19 Age and gender also impact normal QT/QTcintervals. It is thought that sex hormone levels playa role in these QT interval changes.22–25 After pu-berty, men have shorter QT intervals than women,which may be related to increased testosteronelevels. As both genders age, the QT interval grad-ually increases. Progesterone has been reportedto affect HERG trafficking, and postmenopausalwomen treated with estrogen demonstrated pro-longed QT intervals compared with controls.26,27

In addition, female hearts have fewer ion channels,which render them more susceptible to repolariza-tion abnormalities.28 For these reasons, using theBazett formula, a normal QTc is less than 450 msfor men and less than 460 to 470 ms for women.It has been reported that approximately 70% ofall cases of TdP occur in women.20,29–31 Althoughno absolute threshold has been determined toconfer excess risk of TdP, most cases occurwhen the QTc exceeds 500 ms. Therefore, cautionshould be exercised when evaluating patients withQT intervals greater than 500 ms.9,32

Box 2Risk factors for QT prolongation

Increasing age(>65 y)

Female gender

Bradycardia Congestive heart failureLeft ventricularhypertrophy

Congenital long QT syndromes(ion channelopathies)

Drugs Electrolyte disturbances(potassium and magnesium)

Hypothermia HIV infectionIntracranialpathologicabnormality

Connect tissue disorders

For patients with prolonged QT intervals, treat-ment is focused on correcting the underlyingcause. In particular, medications that are knownto prolong the QT interval should be stopped if atall possible. In addition, potassium and magne-sium should both be regularly evaluated andaggressively corrected. Magnesium repletion hasbeen shown to shorten the QT interval as has po-tassium repletion with a goal serum concentrationof 4.5 to 5 mmol/L.33–35

HISTORY OF DRUG-INDUCED QTPROLONGATION AND TORSADES DE POINTES

Antiarrhythmic medications were the first class ofmedications found to prolong the QT interval andincrease the risk of TdP. Syncope associatedwith quinidine exposure was first observed in the1920s; however, TdP was not identified as thecausative mechanism until the 1960s.36 The termTdP was first used by the French cardiologist Des-sertenne37 in 1966 to describe this uniquearrhythmia. Over the next several decades, the as-sociation of QTc prolongation and TdP was identi-fied. It was found to occur relatively frequentlyduring the administration of class III antiarrhythmicmedications, which are known to block IKr, withrates exceeding 1% in some series.38,39 At thesame time, other classes of pharmaceuticalagents, including psychiatric medications and an-tibiotics, were reported to cause TdP; however,the rates were quite low and little attention waspaid to the arrhythmogenic potential of noncardiacdrugs.

The landscape changed dramatically in the fallof 1989 when the first case of QT prolongationand TdP associated with terfenadine administra-tion was reported. Terfenadine was a widely pre-scribed nonsedating antihistamine. Although ithad potent HERG-channel blocking effects, itsimpact on the QTc at standard clinical doseswas insignificant. Further studies revealed that ter-fenadine underwent extensive first-pass hepaticmetabolism by cytochrome P450 3A4 to its activemetabolite, which has no effect on the HERGchannel. In patients with impaired hepatic meta-bolism, systemic terfenadine levels were signifi-cantly elevated, leading to marked QTcprolongation.40,41 Although the exact number ofcases of TdP and death from terfenadine is notcertain, one review cited at least 125 deaths inthe United States from this drug.42 Given thatthis medication treated a benign condition andthere were other safer alternatives, it was ulti-mately withdrawn from the market in 1997. Sincethen, 6 additional drugs have been removed fromthe market for increased rates of TdP and death,

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including the antibiotic grepafloxacin (at least 13arrhythmia-associated deaths43) and the gastro-prokinetic cisapride (80 arrhythmia-associateddeaths reported to the US Food and Drug Admin-istration [FDA])44,45 and many others havereceived updated labeling and/or black boxwarnings.

CORRECTED QT MONITORING ANDREGULATION IN DRUG DEVELOPMENT

Because of the significant consequences associ-ated with the QT prolonging effects of the afore-mentioned drugs, regulatory agencies weredeveloped to provide guidance and oversight inthe drug development process. In 2005, the Inter-national Committee on Harmonization (ICH), amultinational regulatory body, published guidelinesfor QT monitoring of novel non-antiarrhythmicpharmaceutical agents in both the preclinical andthe clinical settings.46,47 These guidelines havesince been adopted by regulatory agencies inboth the United States and the European Union.

Preclinical Assessment

ICH safety guideline 7B (S7B) is the portion of theICH document that deals with drug developmentbefore human administration. The goal of thesepreclinical studies is to identify the potential of adrug and its metabolites to delay ventricular repo-larization. The recommendation is to conduct bothin vitro IKr and HERG assays and in vivo QT ana-lyses using laboratory animals such as caninesor nonhuman primates. The choice of species isimportant because some animals, for examplemice and rats, have very different mechanisms ofrepolarization compared with humans.46 Testsmay be also conducted to evaluate action poten-tial effects in Purkinje or ventricular muscle fibers.When conducting in vitro assays, appropriate pos-itive controls must be used and testing of metabo-lites (separate from the parent compound) shouldbe considered.48 Despite significant improve-ments in these tests, there are several limitations.No gold standard has been established andalthough the sensitivity of these nonclinical testsis quite good, the specificity of these tests hasbeen questioned.49 The degree in which a drug in-teracts with the HERG channel poorly correlateswith the likelihood and extent to which the QT in-terval will be prolonged in the clinical setting. Infact, recent data suggest that simply screeningfor IKr inhibition may not be sufficient; rather,arrhythmogenic potential may more closely linkedto inhibition of the phosphatidylinositide 3-kinasepathway and augmentation of the late sodium cur-rent (INa-L).

50,51 Last, drugs that do not increase

transmural dispersion of repolarization are unlikelyto cause TdP regardless of HERG inhibition or QTprolongation. The issue of transmural dispersion ofrepolarization is not discussed or recommended inthese documents.52,53

Clinical Assessment and the “Thorough QT/Corrected QT Study”

ICH efficacy guideline 14 (E14) is the portion of theICH document that provides guidance about theclinical evaluation of a drug’s effect on ventricularrepolarization and the QT interval. A specific trial,coined the “Thorough QT/QTc Study (TQTS)”should be conducted early in clinical developmentof the pharmaceutical agents. This study is typi-cally conducted in healthy volunteers to determineif a drug has a threshold effect on cardiac repolar-ization. The goal of the TQTS is to exclude a drugprolongs the QTc interval by 10 ms or more at theone-sided upper 95% confidence limit. The resultsof this study will help determine if further testingand evaluation is required during later phases ofdevelopment (ie, if a drug effect exceeding10 ms cannot be excluded). A TQTS is requiredas a part of drug development even if preclinicaltesting is negative for HERG inhibition or QT pro-longation. Until the QT effects of the drug aredelineated, certain exclusion criteria have beenestablished for study volunteers. Those individualswith a prolonged baseline QTc interval (>450 ms)or those with a history of additional risk factorsfor TdP (such as cardiac disease, congenital syn-dromes, or electrolyte abnormalities) should beexcluded from the TQTS.4,47,54

Healthy volunteers receive placebo, a positivecontrol that prolongs the QT interval slightly, thestudy drug at the therapeutic dose as well as ata supratherapeutic dose. This trial is conductedin either a randomized crossover or a parallelfashion. Given that there is less intrasubject vari-ability, the crossover study design is preferableand requires a smaller sample size to exclude aQT prolongation effect. The parallel design maybe preferred if the drug must be dosed for anextended period of time to achieve appropriateserum levels.4,47,54 The placebo drug is includedto account for random variability associated withthe study. The positive control is included toensure adequate sensitivity. It is necessary forthe study to detect changes in the QT intervalas small as 5 ms; changes smaller than this areunlikely to cause TdP.47,54 The fluoroquinolonemoxifloxacin is used as the positive control inthe overwhelming majority of TQTS cases.55

Ideally, the positive control should have a QT pro-longing effect of about 5 ms; however,

QT Prolongation and Oncology Drug Development 7

moxifloxacin typically prolongs the QTc by 8 to15 ms. This excess QT prolonging effect of a pos-itive control is considered acceptable providedthat it is not so long as to hinder the study’s abilityto detect small QTc changes. In addition, the QTprolonging effect of the positive control should besimilar to values obtained in prior TQTS. If theeffect of the positive control is substantiallydifferent, the sensitivity of the current TQTS wouldbe questioned.54

Recent updates to the ICH E14 recommenda-tions have focused on issues of gender represen-tation in these studies and the appropriatealgorithm for QT correction. It is well known thatwomen have longer QT intervals compared withmen, but the exact cause for this difference isnot completely understood. The current recom-mendations suggest equal representation of gen-ders in TQTS and to perform subgroup analysiswhenever a TQTS is positive. Regarding QTcassessment, earlier iterations of the ICH E14 docu-ment did not specifically address which correctionformula should be used during a TQTS. Althoughthe current document does not go so far as torecommend one specific method, they do suggestthat the Fridericia formula is likely to be appro-priate in most situations.56,57

It is important to note that the TQTS is notdesigned to determine the likelihood that a newpharmaceutical will cause TdP. In fact, a positivestudy cannot adequately determine the proar-rhythmia effects of a drug because there is not alinear relationship between the QT interval andthe risk of TdP.9 Rather, the TQTS is conductedto identify those drugs that will require more thor-ough ECG and safety evaluation.

QT/CORRECTED QT MONITORING INONCOLOGY DRUG DEVELOPMENT

It is well recognized that the TQTS cannot beapplied to every new pharmaceutical agent indevelopment. This reasoning holds particularlytrue for oncology drugs and other cytotoxicagents. The E14 guidelines acknowledge that theadministration of chemotherapeutic agents tohealthy volunteers would be unethical.47 As analternative, TQTS-like studies are sometimes con-ducted in target patient populations as part ofphase 1 oncology trials. This can still be a signifi-cant challenge because most oncology patientsenrolled in phase 1 trials have advanced malig-nancies. These patients are often elderly andhave comorbid conditions such as underlying car-diovascular disease that would otherwise excludethem from a TQTS. They are also frequently takingother drugs such as antiemetics and antibiotics,

which can also prolong the QT interval, thus mak-ing accurate interpretation challenging.4,58

Determining reasonable and appropriate inclu-sion and exclusion criteria for these modified QTmonitoring studies for oncology drugs is of signif-icant importance. The guidelines set forth forTQTS is likely far too restrictive for oncology drugstudies. As already indicated, many of these pa-tients have concomitant medical conditions thatcan prolong the QT interval, which would other-wise exclude them from a TQTS. They may alsobe taking other medications with a QT prolongingeffect, which cannot be safely stopped.58 In addi-tion, the QTc cutoff of 450 ms may be too restric-tive for this population. There appears to begreater variability in the QT interval among patientswith cancer compared with healthy controls.These data suggest that if the current QT/QTcexclusion of 450 ms is applied to oncology trials,more than 10% of potential study participantswould be excluded.59,60

Phase 1 oncology trials often have multiple pro-tocol issues that make QTc evaluation challenging.Conversely, the rigorous QTc protocols outlined inthe ICH E14 document can be applied to healthyvolunteer populations but are not appropriatewhen treating patients with advanced cancer.For example, oncology trials are often not random-ized and the administration of either a placebo or apositive control drug would be completely inap-propriate for patients with advanced cancer. Itshould also be recognized that oncology patientsthemselves may be either physically or psycholog-ically incapable of participating in the intensivetime-sensitive ECG collection and cardiac moni-toring necessary for these types of studies.4,58

With this in mind, the E14 document suggeststhat when a TQTS is impossible, other methodsof monitoring the QTc must be developed so asto ensure safety and mitigate risk. This methodcan include extensive preclinical assessment forHERG inhibition and QT prolongation as well asrobust ECG collection at different time points dur-ing the trial itself.4 Some experts suggest applyingthe National Cancer Institute’s toxicity criteria forQTc prolongation (Version 4 of the Common Ter-minology Criteria for Adverse Cardiac Events[CTCAE.v4]) to guide decision-making duringthese studies.61

Based on these criteria, it is recommended todefine dose-limiting toxicity as grade 2 or higherQTc prolongation. These definitions, however,may be too restrictive to guide dosing in oncologypatients. For example, diurnal variation of morethan 60 ms has frequently been observed inoncology patients, and oncology patients have awider range of QTc intervals compared with

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healthy controls.4,62,63 Because the QT interval isso poorly correlated with the development ofTdP, these parameters may unnecessarily preventpatients with cancer from receiving life-savingtherapy. Although it is still mandatory to determinethe QT prolonging effects of cytotoxic agents toensure appropriate patient safety, it is clear thatthe current guidelines cannot be uniformly appliedto oncology drug development.Despite all of this, there remains little uniformity

in the definition, management, and monitoring ofQT interval prolongation in the realm of oncologydrug development. The authors recommend liber-alizing the definition of dose-limiting QTc prolon-gation for oncology trials to grade 3 toxicity orhigher, especially because the overwhelmingmajority of TdP cases occur at QTc values greaterthan 500 ms and those with substantial QTchanges (>100 ms) from baseline. In addition, pa-tients with baseline QTc measurements of 480 msor less should be considered for enrollment inthese trials. Frequent ECG monitoring has notbeen shown to provide significant improvementin the prediction or diagnosis of future cardiacevents.64,65 It would be reasonable therefore toobtain an ECG at baseline (before the initiation ofthe drug), and at least 2 consecutive measure-ments within 48 hours of receiving the drug.Finally, pharmaceutical companies should stan-dardize the method used for QT correction. Giventhe current data, the authors would advocate foruniversal use of the Fridericia formula in oncologydrug development.

CORRECTED QT PROLONGATIONASSOCIATED WITH SPECIFICCHEMOTHERAPEUTIC AGENTSArsenic Trioxide

The medicinal properties of arsenic were first iden-tified by the Chinese as early as the first century BC;however, arsenic’s toxicity profile and associationas a poison have limited itsmedical use in themod-ern era and led to substantial regulations.66 In the1990s, arsenic trioxide was identified as an effec-tive therapy for patients with relapsed or refractoryacute promyelocytic leukemia (APL). APL accountsfor 10% to 15% of all adult acute myeloid leuke-mias, and although first-line therapy with all-trans-retinoic acid has substantially improvedsurvival, 20% to 30% of patients will relapse.67–71

Initial single-center studies reported completeremission rates between 85%and 93% for patientswith relapsed APL treated with arsenic, and theseresults were confirmed in a multicenter study thatreported similar complete remission rates of 85%in patients treated with arsenic.69,72–74

QTc prolongation and TdP are known cardio-vascular complications associated with arsenicpoisoning.75 Several early studies suggested onlyminor asymptomatic ECG abnormalities in APLpatients treated with arsenic trioxide; however,multiple case reports were published of patientswith TdP in the setting of arsenic trioxide treat-ment.72,76,77 Several studies have been conductedto more systematically evaluate arsenic associ-ated cardiotoxicity. In a smaller study from Japan,8 patients treated with arsenic were monitoredwith continuous ambulatory ECG during infusionof the drug. Although all patients in this trial expe-rienced QT prolongation, there were no episodesof sustained VT or TdP.78 In a larger study evalu-ating 99 patients from several different phase 1and phase 2 trials, the risk was significantly lowerwith 38% demonstrating QT prolongation, and26% having a QT greater than 500 ms. Only onepatient had TdP and that was in the setting ofsignificant hypokalemia. In all arsenic trials, themedian daily dose was 0.15 mg/kg with a doserange of 0.06 mg/kg to 0.35 mg/kg.79 A recentstudy evaluating more than 3000 ECGs in 113patients treated with arsenic for non-APL malig-nancies produced similar results: QT prolongationoccurred in 26% of patients with 12% demon-strating a QT interval greater than 500 ms. Despitethis, no clinically significant cardiac events werenoted.80

Although arsenic clearly prolongs the QT inter-val, these studies demonstrate that the risk ofTdP is quite low. Given the great success arsenichas had against relapsed APL, it would be adisservice to withhold this medication based solelyon QTc criteria outlined in regulatory committeedocuments. At this time, labeling instructionsrecommend that arsenic trioxide should bestopped if the absolute QT interval exceeds500 ms or if the patient develops symptoms sug-gestive of ventricular arrhythmias, but it can beresumed if the QT interval decreases to less than460 ms. In addition, the potassium should remaingreater than 4 meq/L and the magnesium greaterthan 1.8 meq/L.81 Arsenic trioxide represents anexcellent example of successful risk mitigationstrategies for a necessary therapeutic.

Molecularly Targeted Agents

Tyrosine kinase inhibitorsProtein kinases are a family of enzymes that regu-lates cellular signaling and function by transferringa phosphate group, typically from ATP, and at-taching it to amino acids with a free hydroxylgroup.82 One group of protein kinases act on tyro-sine, whereas the other group acts on serine and

QT Prolongation and Oncology Drug Development 9

threonine, with a minority of enzymes acting on all3 amino acids. Because of their aberrant activationin multiple types of cancers, protein kinases havebecome important targets for oncology drugdevelopment.82–84 Specifically, small moleculesinhibit tyrosine kinase (TK) enzymes by interferingwith ATP or substrate binding of TKs, thus inhibit-ing their catalytic activity. Such tyrosine kinase in-hibitors (TKIs) are relatively nonselective andgenerally have potency against more than onereceptor TK. In 2001, imatinib (Gleevec), an inhib-itor of BCR-ABL1 chimeric TK aberrantly active inchronic myeloid leukemia (CML), became the firstsuccess story using this strategy by dramaticallychanging the prognosis of CML patients.85 Sincethen, more than 30 TKIs have already been FDAapproved for various cancers with many moreTKIs currently in clinical trials. Although TKIshave been generally well tolerated, specific clas-ses have been associated with cardiotoxicity.86

For example, TKIs that target vascular endothelialgrowth factor receptor (VEGFR) and platelet-derived grown factor (PDGFR) signaling havebeen associated with hypertension, thrombosis,and, less frequently, heart failure.87 In 2013, pona-tinib, which had potent activity against BCR-ABL1kinase, but also against other TKs (includingVEGFR), was temporarily withdrawn from the mar-ket because of vascular toxicity.88 Nilotinib, a TKIwith potent activity against BCR-ABL1 kinaseand FDA approved for treatment of CML, hasbeen associated with peripheral vascular athero-sclerotic disease.89

Several TKIs have been associated with QTprolongation, although incidence of TdP is exceed-ingly rare.84 For example, nilotinib was associatedwith a 5- to 15-ms prolongation of the correctedQT internal in a subset of patients in early clinical tri-als.90 Subsequent follow-up revealed no evidenceof TdP.

Interestingly, QT prolongation associated withTKIs may be more complex than simple inhibitionof the HERG subunit of the IKr channel. Lu and col-leagues50 showed that 3 TKIs associated with QTprolongation in early clinical trials, dasatinib, suni-tinib, and nilotinib, prolonged the action potentialof the cardiac myocytes via inhibition of the phos-phoinositide 3-kinase (PI3K) signaling pathway.Dasatinib, sunitinib, and nilotinib caused anincrease in action potential duration that wasreversed by intracellular infusion of phosphatidyli-nositol 3,4,5-triphosphate in a study using caninemyocytes. PI3K inhibition has downstream effectson many ion channels, including increases in thelate sodium current, INa-L, as well as decreases inthe potassium current via IKr. Experiments usingspecific PI3K inhibitors and transgenic mice with

reduced PI3K signaling, which had prolonged QTintervals at baseline compared with wild-type con-trols, supported a critical role for PI3K signaling.Despite these data, there is no clear class-related QT prolonging effect of TKIs. The chemicalstructure of the TKI may be the only feature thatcan predict the likelihood that the drug will prolongthe QT interval. It has been observed that the pres-ence of a fluorinated phenyl ring on the TKI maylead to an increased risk of QT prolongation andshould lead to more intensive monitoring.84,91

As mentioned previously, the results of preclini-cal data on cardiac repolarization do not alwaystranslate into QT prolongation in the clinical arena.As was the case with nilotinib, this concept appliesto several other drugs in this class. At least 9 of theTKIs carry either standard or black box warningsregarding QT prolongation. Among the TKIs, niloti-nib, vandetanib, and sunitinib are frequently impli-cated for their QT prolonging effects. Sunitinib, asmall-molecule TKI, affects the VEGFR, PDGFR,and c-kit and has been FDA approved in the treat-ment of gastrointestinal stromal tumors and meta-static renal cell carcinoma. Preclinical studiesindicated significant effects on cardiac repolariza-tion, interacting with HERG, and prolonging APduration in Purkinje fibers and the QT interval inprimate studies. In clinical trials, QT prolongationwas only observed with high concentrations ofthe drug; however, no clinical events werereported. The mean increase in the QTc usingthe Fridericia formula was 15.4 ms (90% confi-dence interval 8.4–22.4 ms). Other clinical studieswith sunitinib failed to show any impact on the QTinterval. Some experts suggest that the FDA warn-ings are too restrictive for this medication given theclinical findings.84,92,93

Vandetanib is a potent TKI, which affectingVEGFR-2, RET, and endothelial growth factorreceptor, is FDA approved for the treatment oflocally advanced or metastatic medullary thyroidcancer. Preclinical studies suggested the potentialfor QTc prolongation; this was confirmed inmultipleclinical trials.58,94 Several phase 1 trials reportedQTc prolongation rates between 9% and61%.95,96 In a phase 2 trial assessing vandetanibin combination with docetaxel for patients withdrug refractory non-small-cell lung cancer (NSCLC),the rate of QT prolongation was 15% and all eventswere classified as grade 1 or 2. No clinical eventswere observed and each episode was effectivelymanaged with dose reduction or interruption.97

Several other phase 2 trials confirmed these re-sults.98,99 In a phase 3 trial evaluating vandetanibin patients with advanced NSCLC, QTc prolonga-tion occurred in 5.1% of patients. Although mostevents were asymptomatic, one patient developed

Fradley & Moslehi10

TdP leading to cessation of the drug. QT prolonga-tionwas defined as a singlemeasurement of greaterthan 550 ms or an increase of greater than 100 msfrom baseline, 2 consecutive measurements (within48 hours) that were greater than 500 ms but lessthan 550 ms, or an increase of greater than 60 msbut less than 100 ms from baseline to a value ofgreater than 480 ms.100,101 A large meta-analysisof 9 vandetanib trials reported an incidence of all-grade QTc prolongation of 16.4% and high-gradeQTc prolongation of 3.7% in patients with nonthy-roid cancer compared with 18% and 12% inpatients with thyroid cancer.102 Given these data,vandetanib has a black boxwarning for QTc prolon-gation, and physiciansmust complete the Vandeta-nibRiskEvaluation andMitigationStrategyProgramto prescribe this medication.84

As discussed above, nilotinib is used in thetreatment of Philadelphia chromosome-positiveCML. It targets the BCR-ABL fusion protein,c-Kit, and PDGFR receptors. In preclinicalstudies, cardiac repolarization was affected withthis drug, and clinical studies suggested substan-tial QT prolonging effects. In healthy volunteers,the mean QTc change was 18 ms; however, pro-longation of more than 60 ms (using the Fridericiaformula) was reported in 1.9% of CML-chronicphase patients and 2.5% of CML-acceleratedphase patients.58,103 Sudden cardiac death hasbeen reported in approximately 0.3% of patientstreated with nilotinib. Abnormal ventricular repo-larization is thought to have contributed to theseevents, and as a result, nilotinib has received ablack box warning for QTc prolongation.104

Histone deacetylase inhibitorsHistone deacetylase inhibitors (HDI) are group ofmolecularly targeted pharmaceutical agents thatmodulate the posttranscriptional activity of pro-teins by inactivating histone deacetylase enzymes.The resultant abnormal proteins are stuck in G1

and G2 of the cell cycle, leading to apoptosis.105

QTc prolongation has been observed with someHDIs and is thought to be due to interaction withthe HERG channel. A recent study confirmed thatthe pharmacophere for HERG and histonedeacetylase-1 is quite similar, suggesting onepossible reason for the QT prolonging effects ofsome HDIs.106 Vorinostat is an HDI with FDAapproval for the treatment of cutaneous T-cell lym-phoma. In a phase II study, 3 patients wereobserved to have grade 1 or 2 QTc prolongationwithout any clinical sequelae or need for doseadjustment.107 There is one case report of aseverely prolonged QT interval leading to polymor-phic ventricular tachycardia in a patient treatedwith vorinostat; however, this patient also had

concomitant hypokalemia.108 Depsipeptide, alsoknown as romidepsin, is an HDI used to treat a va-riety of malignancies including T-cell lymphoma.Romidepsin can cause QT prolongation, andalthough sudden cardiac death has been reportedin several studies, this association with QT prolon-gation is not certain because most patients hadmultiple risk factors for sudden cardiac arrestand the QT interval was not clearly documentedbefore the event.58,60,93 In a study of patientswith T-cell lymphoma, the mean QTc prolongation(using the Bazett formula) was 14 ms in patientsreceiving romidepsin.60 Oral panobinostat isanother HDI known to impact HERG activity andincrease the Fridericia QTc up to 20 ms in adose-related fashion without clinical sequelae.93

Although these data confirm HDI-associated QTcprolongation, this has not translated into increasedclinical risk.

Other Chemotherapeutic Agents

Left ventricular dysfunction is the most commonlyrecognized cardiotoxicity of anthracyclines; how-ever, these chemotherapeutics can also causeQTc prolongation. In a study evaluating patientswith non-Hodgkin lymphoma treated with epirubi-cin, all patients experienced some degree of QTcprolongation. The QTc prolonging effects weremitigated when concomitant dexrazoxane wasgiven to the patients, however.109 In a Finnishstudy, 18% of patients exposed to doxorubicinexperienced QTc prolongation of greater than50 ms. These changes were independent of LVfunction.110 Tamoxifen has also been shownto cause QTc prolongation in both clinical andpreclinical studies, likely related to HERGinteraction.111

Several other classes of molecularly targetedagents are still relatively early in their development.Certain vascular disruption agents such as CA4P(combrestatin) have been shown to prolong theQTc in clinical trials, whereas others (plinabulin)have not shown this effect.58,112 Therefore, QTcprolongation does not appear to be a class-related effect of the vascular disruption agents.A similar finding has been observed with farnesylprotein transferase inhibitors. The agentL-778123 has been shown in several trials toinduce QTc prolongation without clinicalsequelae.113–115 In contrast, there are conflictingdata regarding lonafarnib because QTc prolonga-tion has been noted in some studies but notothers.93 Last, inhibitors of the serine/threoninekinase, protein kinase C (PKC), have been shownto cause QT prolongation. Overexpression ofPKC has been implicated in many different

QT Prolongation and Oncology Drug Development 11

malignancies including hepatocellular cancer, co-lon cancer, and diffuse large B-cell lymphoma.58

Enzastaurin is a potent selective inhibitor of PKC;however, phase I and II studies have documenteddose-limiting QTc prolongation without clinicalconsequence.116,117

SUMMARY

Safety and efficacy are the 2 paramount aspects ofdrug development. In general, the benefits of thepharmaceutical agent should outweigh any riskassociated with it. In most instances, even a smallrisk of a serious complication cannot be tolerated.QTc monitoring is a central part of the drug-approval process, and most pharmaceuticalagents are subjected to the TQTS, a protocol es-tablished by the ICH to ensure appropriate QTcevaluation. Although it is well known that the QT in-terval is a poor surrogate for TdP, the potential forthis life-threatening arrhythmia in the setting of aprolonged QTc has led to the withdrawal of severaldrugs from the market and more intense labelingand warnings for many others. This issue becomesmore complex when dealing with oncology phar-maceutical agents because the disease is oftenlife threatening and alternative therapies may notexist. A true TQTS cannot typically be performedwith cytotoxic agents and oncology patients arenot an ideal population in which to rigorously testthese drugs. Although the TQTS has been adaptedto evaluate the QT interval and provide oversightfor new chemotherapeutics, it will be necessaryto develop dedicated protocols to appropriatelyevaluate cancer therapeutics. Many of these drugshave been shown to have excellent antitumor effi-cacy, and although QTc prolongation may be pre-sent, implementing appropriate risk mitigationstrategies allow these patients to receive life-saving therapies without exposure to seriousincreased risk.118

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