the ability to balance both efficacy and safety is critical for patient survival and quality of life .
cancer therapy is becoming increasingly specialized , having evolved from using cytotoxic drugs on dividing cells to targeting specific molecular events involved in oncogenic proliferation . among these targeted therapeutics
tyrosine kinases are enzymes that catalyze phosphorylation of target proteins , signaling cellular processes such as growth and proliferation .
unregulated tyrosine kinase activation , therefore , can cause uncontrolled cellular proliferation , leading to cancer .
although complete inhibition of tyrosine kinases may disrupt vital cellular signaling , targeted tkis may prevent cancerous proliferation while sparing essential kinase activity [ 1 , 2 ] .
linifanib is a novel receptor tki with specificity for the vascular endothelial growth factor ( vegf ) and platelet - derived growth factor ( pdgf ) receptors
. it does not possess significant activity against cytosolic tyrosine kinases or serine / threonine kinases . as tumor progression
can rely on both vegf and pdgf signaling , a selective inhibitor could result in high antitumor activity without interrupting other kinase signaling pathways .
in clinical trials , linifanib has demonstrated anti - tumor activity in advanced solid tumors including non - small cell lung cancer ( nsclc ) , renal cell cancer , hepatocellular cancer , colorectal cancer , and breast cancer [ 511 ] . in a double - blind , randomized phase 2 trial ,
the addition of linifanib to carboplatin and paclitaxel resulted in significant improvement in response rates and progression - free survival in patients with advanced nsclc .
a number of drugs have been developed to target specific tyrosine kinases known to be active in certain cancers .
some tyrosine kinases are essential for cardiac function , however . as a result , a side effect of tki treatment has been development of cardiac events , such as a delay in cardiac repolarization [ 2 , 12 , 13 ] .
prolongation of the qt interval ( duration of ventricular depolarization and subsequent repolarization ) may increase the risk of torsade de pointes or other ventricular tachyarrhythmias .
although a number of tkis have been associated with qt prolongation , the majority of tkis do not lead to appreciable qt prolongation at clinical doses [ 1417 ] .
many of these studies , however , have not been conducted in oncology patients , who may be at a greater risk due to concurrent or previous therapies .
it was therefore the objective of this high - precision qt study to investigate the effect of linifanib on qt prolongation in patients with advanced solid tumors .
a phase 1 , single dose , open - label , randomized study in subjects with advanced solid tumors was conducted on 24 patients .
this study was performed in accordance with the ethical standards laid down in the declaration of helsinki .
eligibility included age  > 18  years , ecog performance status scores of 01 , and adequate organ function .
for the assessment of ecgs , patients were randomly assigned to 2 sequences of regimens of linifanib at the maximum tolerated dose , 0.25  mg / kg , without exceeding 17.5  mg , administered orally in a two - period ( day 1 and day 7 ) crossover fashion .
a single 12-lead resting ecg was obtained within the week before day 1 , or on day 1 , and at study completion , or upon subject discontinuation .
triplicate ecgs were obtained serially on day-1 at the anticipated time points for subsequent dosing and before and after dosing on day 1 and day 7 ( crossover period 1 and period 2 , respectively ) .
the time points for measurements were pre - dose and 0.5 , 1 , 2 , 3 , 4 , 6 , 8 , 10 , 12 , and 24  h post - dose .
pharmacokinetic plasma samples were also collected for 72  h on day 1 and day 7 .
qt , rr , pr , and qrs intervals were measured for each ecg using abbvie s validated pc - based algorithm ( abbios ) , with standardized manual over - reading of all ecgs by trained technicians and t  u morphology assessment by cardiologists .
qtc was determined using fridericia s correction method ( qtcf):\documentclass[12pt]{minimal } 
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				 \begin{document}$${\text{qt}}_{f } = \frac{\text{qt}}{{\sqrt{\text{rr}}}}$$\end{document}values for the triplicate ecgs were averaged to obtain a single - interval measurement for each time point .
a linear mixed - effects model was used for the analysis of the day 1 and day 7 data to evaluate the effect of linifanib on cardiac repolarization .
the analysis was performed for time - matched baseline - adjusted qtcf intervals ( qtcf ) . for assessment of the effect of linifanib ,
the primary endpoint was the largest time - matched difference for qtcf between drug regimens and baseline ( qtcf ) .
an intersection  union test was performed at a significance level of 0.05 within the framework of the corresponding mixed - effects model .
linifanib was considered to have a negative effect on cardiac repolarization if at all time points of the ecg measurements , the mean qtcf for linifanib , did not exceed the baseline mean by 10  ms or more with statistical significance level of 0.05 .
therefore , the maximum 95  % upper confidence bound for the baseline - adjusted qtcf ( qtcf ) must be less than 10  ms in order to demonstrate a negative qtc effect . the intersection  union test required high operational and statistical precision of the data to meet the criteria for negative qt effect , since the confidence intervals would be narrower with tighter variability .
additionally , the relationship between baseline - adjusted qtcf and plasma drug concentration was explored using an exposure  response analysis .
the equation for the response variable qtcf ( y ) is:\documentclass[12pt]{minimal } 
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				 \begin{document}$$y = \ , \mu \
, + \alpha\,^ { * } \,{\text{baseqtcf } } + { \text{sequence } } + { \text{hour } } + { \text{day } } + \ , \beta\,^{*}\ , { \text{concentration } } + \ , \eta_{i } + \varepsilon_{ijk}$$\end{document } the model has terms for the baseline measurement ( baseqtcf ) , sequence ( sequence ) , day of measurement ( day ) , and time of measurement ( hour ) .
the random components of this model are denoted by i and ijk , with i identifying the ith subject , j identifying the day , and k identifying the time of the measurement within a day . within the frame work of this model ,
the 95  % upper confidence bound for the effect of the mean cmax of the linifanib dose on the qtcf was provided .
if the bound is less than 10  ms , the regimen does not have a clinically relevant effect on cardiac repolarization .
no subject had qtcf values greater than 500  ms , and no subject had a change greater than 60  ms from baseline .
one subject had an asymptomatic qtcf change of greater than 30  ms from baseline . among the study population ,
after patients received linifanib , the qtcf for the fasting regimen ranged from 4.14 to 0.64  ms , whereas the non - fasting regimen ranged from 6.03 to 1.57  ms ( table  1 ) . the maximum 95  % upper confidence bound for the drug effects for linifanib was 4.30  ms .
these results are below the threshold of regulatory concern as indicated in ich e14 guidance for industry .
it was therefore concluded that linifanib had no effect on cardiac repolarization.table  1intersection  union test results for linifanib on qtcfregimenstime point ( h)qtcf meanpoint 
 estimate95  % upper confidence bounddrugbaselinelinifanib fasting regimen0.5421.8423.92.231.431422.0423.11.242.432422.1421.40.574.243422.6421.90.644.304418.1422.41.921.786415.8419.94.140.478417.5420.22.820.8510419.6420.40.583.1212420.1420.20.163.5024422.1423.51.532.14linifanib non - fasting regimen0.5419.8423.94.150.481418.3423.14.891.232417.1421.44.330.673416.0421.96.032.364413.8422.43.820.126416.9419.93.050.618416.4420.23.870.2010417.2419.41.831.9012417.3418.91.781.9224421.0422.41.572.14 
  qtcf interval change form baseline ( qtcf ) of the least squares means ( msec ) intersection  union test results for linifanib on qtcf 
  qtcf interval change form baseline ( qtcf ) of the least squares means ( msec ) analysis was also performed with linifanib concentration as the drug exposure variable .
the mixed - effects model showed a linear relationship between changes in qtcf interval and linifanib concentration ( fig .  1 ) .
the model estimated a slope of 0.01048 with a standard error of 0.006537 ( p  =  0.1094 ) .
this predicted a trend toward a change in qtcf interval of 3.56  ms at a concentration of 0.34  g / ml ( the cmax at the maximum tolerated dose ) and a 95  % upper confidence bound of 7.2  ms .
in addition to supporting the finding that linifanib does not significantly affect qt interval , this model may provide useful predictions about the impact of other dosing regimens on qt prolongation.fig . 
1linifanib concentration versus qtcf change from baseline ( qtcf ) linifanib concentration versus qtcf change from baseline ( qtcf ) a morphological evaluation was performed for t and u waves at each ecg data collection time point .
no clinically significant morphological changes in ecg , including no abnormal u waves , were observed following linifanib treatment .
isolated non - specific t wave abnormalities were seen and expected in patients who may have previously undergone cytotoxic cancer treatments .
among the study population , baseline qtcf values ranged from 360.9 to 468.6  ms .
after patients received linifanib , the qtcf for the fasting regimen ranged from 4.14 to 0.64  ms , whereas the non - fasting regimen ranged from 6.03 to 1.57  ms ( table  1 ) . the maximum 95  % upper confidence bound for the drug effects for linifanib was 4.30  ms .
these results are below the threshold of regulatory concern as indicated in ich e14 guidance for industry .
it was therefore concluded that linifanib had no effect on cardiac repolarization.table  1intersection  union test results for linifanib on qtcfregimenstime point ( h)qtcf meanpoint 
 estimate95  % upper confidence bounddrugbaselinelinifanib fasting regimen0.5421.8423.92.231.431422.0423.11.242.432422.1421.40.574.243422.6421.90.644.304418.1422.41.921.786415.8419.94.140.478417.5420.22.820.8510419.6420.40.583.1212420.1420.20.163.5024422.1423.51.532.14linifanib non - fasting regimen0.5419.8423.94.150.481418.3423.14.891.232417.1421.44.330.673416.0421.96.032.364413.8422.43.820.126416.9419.93.050.618416.4420.23.870.2010417.2419.41.831.9012417.3418.91.781.9224421.0422.41.572.14 
  qtcf interval change form baseline ( qtcf ) of the least squares means ( msec ) intersection  union test results for linifanib on qtcf 
  qtcf interval change form baseline ( qtcf ) of the least squares means ( msec )
the mixed - effects model showed a linear relationship between changes in qtcf interval and linifanib concentration ( fig .  1 ) .
the model estimated a slope of 0.01048 with a standard error of 0.006537 ( p  =  0.1094 ) .
this predicted a trend toward a change in qtcf interval of 3.56  ms at a concentration of 0.34  g / ml ( the cmax at the maximum tolerated dose ) and a 95  % upper confidence bound of 7.2  ms .
in addition to supporting the finding that linifanib does not significantly affect qt interval , this model may provide useful predictions about the impact of other dosing regimens on qt prolongation.fig . 
1linifanib concentration versus qtcf change from baseline ( qtcf ) linifanib concentration versus qtcf change from baseline ( qtcf )
a morphological evaluation was performed for t and u waves at each ecg data collection time point .
no clinically significant morphological changes in ecg , including no abnormal u waves , were observed following linifanib treatment .
isolated non - specific t wave abnormalities were seen and expected in patients who may have previously undergone cytotoxic cancer treatments .
maintaining cardiac function in patients undergoing cancer treatments is a concern in the development of any new drug .
advancements in molecular medicine have provided a number of attractive targets in the tyrosine kinase family of growth and proliferation signaling enzymes . in some cases , however , these drugs can interfere with cardiac repolarization and may pose a risk to patients who have undergone or are currently on cancer therapy .
the current study is one of a few to rigorously test the effect of an investigational drug on cardiac repolarization in patients with advanced tumors who are refractory to standard treatments .
analysis of the resulting data has concluded that linifanib does not pose a heightened risk for qtc prolongation in this refractory patient population . despite a sample size of 24 subjects , the data had high operational and statistical precision as the 95  % upper confidence bounds for mean differences from baseline were below the threshold of regulatory concern at all time points .
response modeling showed qtcf change was not significant at the maximum concentration for the maximum tolerated dose , which further supports a lack of qt prolongation with linifanib .
there were also no significant t or u wave morphological changes as determined by trained investigators . a categorical analysis of subjects with an absolute qtcf value in excess of 500  ms or change in baseline for more than 3060  ms supports the absence of clinically significant effects .
more broadly , at the time of this analysis , no significant adverse events related to abnormal cardiac repolarization were reported in this trial nor the concurrent phase 1 , 2 , and 3 clinical trials , representing an analysis of more than 700 linifanib - treated patients ( data on file ) .
 purposelinifanib is a selective inhibitor of the vascular endothelial growth factor and platelet - derived growth factor family of tyrosine kinase inhibitors . 
 the purpose of this high - precision qt study was to evaluate the effects of linifanib on cardiac repolarization in patients with advanced metastatic tumors.methodsenrolled patients ( n  =  24 ) had measurable disease refractory to standard therapies , ecog performance status of 01 , and adequate organ function . 
 patients were randomized in a 2-sequence , 2-period crossover design . 
 serial ecg measurements and pharmacokinetic samples were collected for each crossover period . 
 an intersection  union test was performed for time - matched baseline - adjusted qtcf intervals . 
 an exposure  response analysis was explored to correlate the plasma concentration and qtcf.resultsthe maximum 95  % upper confidence bound for the baseline - adjusted qtcf was 4.3  ms at hour 3 at the maximum tolerated linifanib dose of 0.25  mg / kg . 
 linifanib did not meet the regulatory threshold ( 10  ms ) for qt prolongation . 
 exposure  
 response modeling showed that the qtcf change was not significant at the maximum plasma concentration.conclusionslinifanib does not significantly affect cardiac repolarization in patients with advanced solid tumors . 