Study Day 1 Study Days 2 to 9 Sequence 1 Placebo for moxifloxacin Study Days 2 to 8: placebo for pazopanib (placebopaz) 800 mg;

Transcription

1 The study listed may include approved non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No: VEG Title : A Phase I, Romized, Double-Blinded, Placebo-Controlled Study to Evaluate the Effect of Repeat Oral Doses of (GW786034) on Cardiac Conduction in Subjects with Solid Tumors Rationale: Previous preclinical assessments of pazopanib suggested that the risk for QT interval prolongation in humans at therapeutic concentrations was likely to be low. Clinical cardiac safety evaluations have not ruled out an effect on the corrected QT (QTc) interval associated with the administration of pazopanib; although a retrospective study found no apparent relationship between pazopanib concentrations the QT interval, it was limited by the absence of placebo positive controls. Given that QTc prolongation has been reported with other vascular endothelial growth factor receptor (VEGF) inhibitors; this study was conducted to evaluate the effect of pazopanib on electrocardiogram (ECG) parameters. Phase: I Study Period: 19 March February 2010 Study Design: Romized, double-blind, placebo-controlled, positive-controlled, parallel group, multicenter study. Centres: 8 centers in the United States Indication: Cancer Treatment: Subjects received either moxifloxacin or placebomoxi on Study Day 1 either pazopanib or placebopaz on Study Days 2 to 9 according to their romization to one of 4 treatment sequences. Treatment Study Day 1 Study Days 2 to 9 Sequence 1 Placebo for moxifloxacin Study Days 2 to 8: placebo for pazopanib (placebopaz) 800 mg; (Placebomoxi) Study Day 9: placebopaz 1600 mg 2 Placebo for moxifloxacin Study Days 2 to 8: pazopanib 800 mg; (Placebomoxi) Study Day 9: pazopanib 1600 mg 3 Moxifloxacin 400 mg Study Days 2 to 8: placebopaz 800 mg; Study Day 9: placebopaz 1600 mg 4 Moxifloxacin 400 mg Study Days 2 to 8: pazopanib 800 mg; Study Day 9: pazopanib 1600 mg Objectives: The primary objective was to estimate the effect of pazopanib on the baseline-adjusted, time-matched Fridericia-corrected QT interval (QTcF) as compared with placebo in the Evaluable Population. The secondary objectives were to characterize the relationship between plasma concentrations of pazopanib its metabolites ECG parameters (QT, QTcF, Bazett-corrected QT interval [QTcB]) between plasma concentrations of moxifloxacin ECG parameters (QT, QTcF QTcB); to estimate the effect of a single 400 mg dose of moxifloxacin on baseline adjusted, time-matched QTcF interval as compared with placebo; to describe the shortterm safety of repeated daily oral doses of pazopanib 800 mg as compared with placebo the acute safety of a single oral 1600 mg dose of pazopanib administered in the presence of food. Statistical Methods: Change from time-matched baseline QTcF values at each time point on Study Day 9 on Study Day 1 was analyzed separately by linear mixed-effects model for the comparison between pazopanib placebopaz for the comparison between moxifloxacin placebomoxi. Similar analyses were conducted for QTcB individual corrected QT interval (QTci). Other ECG parameters were listed summarized descriptively by treatment. Linear mixed-effect modeling was performed to explore the relationship between pazopanib its metabolites concentration the QTcF interval. No formal statistical analysis was performed on safety data pharmacokinetic (PK) data. Safety data including adverse events (AEs), serious AEs (SAEs), clinical chemistry, hematology, vital signs, Eastern Cooperative Oncology Group (ECOG) performance status safety ECGs were listed summarized by treatment. PK concentration data were listed summarized by planned time, PK parameter data were listed summarized. Given the peak effect of pazopanib on QTcF interval was observed at the last planned time point of 8-hours (hrs) postdose, a post-hoc analysis was performed to determine whether a larger effect of pazopanib on the QT/QTc interval was present between 8 24-hrs post-dose. Holter ECG data were extracted on Study Days -1 9 analyzed in a similar manner as the original planned analysis. In addition to analyses of QT/QTc interval, analyses comparing change from baseline in HR PR interval between pazopanib placebopaz were conducted separately by linear 1

2 mixed-effects modeling. The All Subjects Population consisted of all subjects who received at least 1 dose of study treatment (used for Safety analysis). The Evaluable Population included subjects from the All Subjects Population who met all eligibility criteria; maintained double-blind treatment allocation through Study Day 9; received study treatment on Study Days 1, 8 9 a minimum of 5 doses of study treatment during Study Days 2 through 7; completed Holter ECG acquisitions through the 8-hr time point on Study Days -1, 1 9 (used for ECG analysis). The Pharmacodynamic (PD) Population included subjects from the All Subjects Population who completed ECG acquisitions via Holter monitoring on at least 1 time point on 1 of the following study days: Study Days -1, 1 or 9 (used for ECG analysis). For the Post-Hoc Analysis, the 24-hr Evaluable Population included all subjects from the All Subjects Population who met all eligibility criteria, maintained double-blind treatment allocation through Study Day 9, received study treatment on Study Days 1, 8 9 a minimum of 5 doses of study treatment during Study Days 2 through 7, completed Holter ECG acquisitions through the 8-hr time point on Study Days -1, 1 9, had available Holter ECG data obtained via Holter monitoring for all 4 time points in the 8 to 24-hr post-dose time period: 12, 16, hrs postdose on Study Days 1 9. The Non-24 hr Evaluable Population consisted of subjects from the All Subjects Population who did not meet the 24-hr Evaluation Population criteria. NOTE: The number of subjects (represented by N or n ) used in the tables below may vary as subjects may have been excluded from the specific subject population to derive the value based on population definition, missing values, or inclusion in more than one category Study Population: Male or female subjects, 18 years of age or older, with solid tumor malignancies ECOG performance status of 0 or 1 were eligible. Subjects were required to have adequate hematologic, renal, hepatic function; in addition, serum potassium, magnesium calcium levels were to be within normal limits. Women of childbearing potential were permitted in the study if adequate approved contraceptive means were used. Subjects were not eligible for inclusion if they had QTcF interval >470 msec, PR interval >240 msec or 110 msec, or bradycardia (sinus rate <50 beats per minute [bpm]); cardiac conduction abnormalities (second or third-degree atrioventricular block, ventricular pre-excitation, complete left bundle branch block, intraventricular conduction delay with QRS duration >120 msec, atrial fibrillation, or presence of cardiac pacemaker). History of Class III or IV congestive heart failure, cardiac angioplasty or stenting, myocardial infarction, unstable angina, or symptomatic peripheral vascular disease or other clinically significant cardiac disease within 6 months of study entry also excluded subjects from participation in the study. Subjects with left ventricular ejection fraction <50%, history of long-qt syndrome, or poorly controlled hypertension (>140/90 mmhg) were also excluded. Number of Subjects: It was estimated that 80 subjects would be enrolled to ensure a minimum of 60 evaluable subjects who completed the study. Sample size calculation was made assuming an estimation approach to address the objective of estimating the effect of pazopanib on QTcF interval as compared with placebo. Treatment Sequence 1 Treatment Sequence 2 Treatment Sequence 3 Treatment Sequence 4 Planned N Dosed N Completed n (%) 24 (100) 24 (100) 23 (96) 24 (100) Total Number of Subjects Withdrawn n (%) (4) 0 Reason for Subject Withdrawal n (%) Adverse Event (4) 0 Number of Subjects Entering Rollover 23 (96) 22 (92) 23 (96) 24 (100) Study n (%) Number of Subjects Not Entering Rollover 1 (4) 2 (8) 1 (4) 0 Study n (%) Reasons for Not Entering Rollover Study n (%) Did not meet inclusion/exclusion 0 1 (4) 0 0 criteria Adverse Event (not specified) 1 (4) 1 (4) 0 0 Other, specify (4) a 0 a Subject died due to disease under study prior to enrolling in the rollover study, VEG

3 Demographics Study Day 1: All Subjects Population Study Days 2 to 9: All Subjects Population Placebomoxi Moxifloxacin n Sex Females: Males 18:30 28:20 23:24 23:25 Age in years Mean (SD) 58.8 (9.96) 56.7 (13.52) 56.1 (12.79) 59.0 (10.71) Median (Min - Max) 61 (33, 78) 58 (22, 79) 56 (27, 78) 61 (22, 79) Weight in kg Mean (SD) 78.8 (16.04) 73.6 (13.86) 78.6 (17.08) 73.9 (12.90) Median (Min - Max) 78.8 (47-115) 74.7 (46 109) 80.5 (46 115) 74.7 (51, 104) Race White, n (%) 44 (92) 43 (90) 43 (91) 43 (90) African-American/African Heritage, n (%) 3 (6) 4 (8) 3 (6) 4 (8) Asian Japanese/East Asian Heritage, 1 (2) 1 (2) 1 (2) 1 (2) n (%) Ethnicity Hispanic or Latino, n (%) 3 (6) 2 (4) 3 (6) 2 (4) Not Hispanic or Latino, n (%) 45 (94) 46 (96) 44 (94) 46 (96) Abbreviation: max, maximum; min, minimum; SD, stard deviation Pharmacokinetics (PK) Endpoints: The summary statistics for PK parameters of moxifloxacin following single dose administration pazopanib its metabolites (GSK , GSK GSK ) following repeatdose administration are summarized in the following tables: Summary of PK Parameters for Moxifloxacin on Study Day 1 (PK Parameter Population) Study Visit N PK Parameters AUC(0-8) Cmax Tmax ( g*hr/ml) a,c ( g/ml) a (hr) b Study Day (10.8, 13.9) 2.44 (2.22, 2.68) 2.00 ( ) a. Data presented as geometric mean (95% confidence interval [CI]) b. Data presented as median (range) c. n = 47 Summary of PK Parameters for Metabolites on Study Day 9 (PK Parameter Population) PK Parameters n GSK GSK GSK AUC(0-24) ( g*hr/ml) a (1260, 1590) (45.7, 60.4) (26.3, 37.4) (13.9, 19.7) Cmax ( g/ml) a (69.9, 87.4) (2.32, 3.02) (1.71, 2.43) (0.745, 1.05) tlast (hr) b 24.1 (22.7, 25.0) 24.1 ( ) 24.1 ( ) 24.1 ( ) Tmax (hr) b 6.0 ( ) 6.0 ( ) 4.0 ( ) 6.0 ( ) a. Data presented as geometric mean (95% CI) b. Data presented as median (range) Pharmacodynamics (PD) Endpoints: For the moxifloxacin-treated subjects in the Evaluable Population, the plasma levels following administration of moxifloxacin 400 mg were in the anticipated range. The administration of moxifloxacin on Study Day 1 caused a prolongation of the QTcF interval at 3-, 4-, 6-8-hrs post-dose based on results from the mixed-effect model for the Evaluable Population. For moxifloxacin-treated subjects in the Evaluable Population, the maximum mean difference in the baseline-adjusted, time-matched QTcF interval compared to placebo was msec (90% CI 4.2, 17.03) seen at 3-hrs post-dose. In the PD Population, the maximum QTcF effect was msec (90% CI 5.82, 16.81) at 8-hrs post-dose. The magnitude of the moxifloxacin effect is consistent with previously reported literature confirms sensitivity of this study design to detect changes in the QTcF interval. 3

4 Summary of Statistical Analysis of the Placebo-Corrected, Baseline-Adjusted, Time-Matched QTc, Mean Difference (90% CI) for Subjects Administered Moxifloxacin or Placebo on Study Day 1 (Evaluable Population PD Population) Time Point QTcF Treatment Difference (90% CI) QTcB QTci Evaluable Population (N = 65) -0.5 Hr (-8.04, 5.14) 1.54 (-5.21, 8.30) 0.12 (-7.22, 7.47) 1 Hr 5.94 (-.0.47, 12.36) 7.39 (0.85, 13.93) 7.21 (0.01, 14.41) 2 Hr 5.28 (-1.13, 11.70) 4.40 (-2.14, 10.94) 6.00 (-1.20, 13.20) 3 Hr (4.20, 17.03) (5.17, 18.24) (4.73, 19.11) 4 Hr 9.30 (2.89, 15.72) (3.59, 16.68) 9.42 (2.23, 16.61) 6 Hr 6.93 (0.51, 13.35) 6.88 (0.34, 13.42) 7.75 (0.56, 14.95) 8 Hr 9.26 (2.84, 15.68) (6.63, 19.71) (3.89, 18.28) PD Population (N = 96) -0.5 Hr 0.53 (-5.12, 6.17) 0.68 (-4.87, 6.24) 0.82 (-5.06, 6.70) 1 Hr 8.12 (2.63, 13.61) 8.60 (3.25, 13.95) 8.34 (2.61, 14.07) 2 Hr 8.85 (3.36, 14.34) 8.65 (3.30, 14.00) 8.86 (3.14, 14.59) 3 Hr (5.27, 16.25) (6.58, 17.28) (5.69, 17.14) 4 Hr (4.78, 15.74) (5.79, 16.48) (4.40, 15.83) 6 Hr (5.36, 16.34) (5.16, 15.85) (4.79, 16.23) 8 Hr (5.82, 16.81) (7.50, 18.21) (5.70, 17.14) Abbreviations: CI, confidence interval; Hr, hour; msec, milliseconds caused clinically significant increases in systolic diastolic blood pressure noted at 8-hr time point on Study Day 9 a concomitant but variable reduction in heart rate. Hypertension, a known PD effect for this class of agents, was reported as an AE for 7 (15%) subjects (see Safety) required a change in anti-hypertensive therapy in 6 of 7 subjects (5 subjects had an increase in dose of antihypertensive medication 1 subject had antihypertensive therapy initiated). Summary of Blood Pressure Heart Rate Maximum Changes for on Study Days -1 9 (All Subjects Population) Treatment Study Day -1 a Study Day 9 a Maximum Change a Blood Pressure (mmhg) Group (N = 47) (N = 48) Heart Rate (bpm) (N = 47) (N = 48) Abbreviations: hr, hour; bpm, beats per minute; mmhg, millimeters of mercury a. Values are mean stard deviation b. n = 47 c. n = 48 d. n = 45 (8-hr time point) (8-hr time point) / / / d 9.66 b 8.61 d / / / d 8.79 c 8.37 d b d d c d d 4

5 From the mixed-effect model, the maximum difference in heart rate between pazopanib placebo in the timematched change from baseline (mean difference, 90% CI) based on Holter ECG heart rate data was seen at 8-hrs in both the Evaluable Population (-8.21 bpm [90% CI , -3.68]) as well as the PD population (-9.86 bpm [90% CI , -5.80]). In view of the unexpected variable effect of pazopanib on heart rate, as well as the known dependence of QTc duration on RR interval, the QTci was calculated as an exploratory endpoint for each subject, in addition to the prespecified QTcF, QTcB intervals. Examination of the relationship with RR interval (from Holter ECG data) showed that QTci is the least dependent on RR interval followed by QTcF, then QTcB. Summary of Regression Coefficient Estimate for RR from Repeated Measures Statistical Analysis of QT, QTcF, QTcB, QTci (PD Population, N = 96) Parameter Regression Coefficient Estimate Using Baseline Data Estimate 95% CI QT , QTcB , QTcF , QTci , Abbreviation: CI, confidence interval Using the mixed-effect model for pazopanib-treated subjects in the Evaluable Population, the maximum mean difference in baseline-adjusted, time-matched QTcF interval compared to placebo was 4.43 msec (90% CI -2.36, 11.22) at 8-hrs post-dose on Study Day 9 in the PD Population, the maximum QTcF effect was 4.33 msec (90% CI -1.29, 9.94) at 8-hrs post-dose. Summary of Statistical Analysis of the Placebo-corrected, Baseline-adjusted, Time-matched QTc, Mean Difference (90% CI) for Subjects Administered or Placebo on Study Days 2 to 9 (Evaluable Population PD Population) Time Points on Study Day 9 QTcF Evaluable Population (N = 65) -0.5 Hr (-7.10, 6.70) 1 Hr 3.96 (-2.82, 10.74) 2 Hr 1.96 (-4.82, 8.74) 3 Hr 2.10 (-4.69, 8.88) 4 Hr 1.42 (-5.36, 8.21) 6 Hr 4.33 (-2.45, 11.11) 8 Hr 4.43 (-2.36, 11.22) PD Population (N = 95) -0.5 Hr 0.48 (-5.22, 6.19) 1 Hr 2.89 (-2.70, 8.48) 2 Hr 1.20 (-4.42, 6.82) 3 Hr 2.16 (-3.47, 7.78) Treatment Difference (90% CI) QTcB (-8.83, 6.26) (-8.39, 6.41) (09.30, 5.52) (-9.48, 5.33) (-9.77, 5.04) (-10.39, 4.42) (-10.61, 4.19) (-7.83, 4.88) (-8.76, 3.65) (-9.53, 2.97) (-9.36, 3.14) QTci (-8.50, 6.73) 1.85 (-5.65, 9.35) 0.51 (-6.99, 8.00) 0.73 (-6.77, 8.23) 0.22 (-7.29, 7.72) 1.22 (-6.28, 8.72) 1.71 (-5.79, 9.21) (-8.56, 4.76) 1.06 (-6.50, 6.61) (-7.78, 5.38) (-7.03, 6.14) 4 Hr

6 (-5.20, 6.05) (-10.24, 2.24) (-8.51, 4.66) 6 Hr 3.66 (-1.96, 9.28) (-10.72, 1.76) (-6.89, 6.27) 8 Hr 4.33 (-1.29, 9.94) (-11.29, 1.18) 0.52 (-6.05, 7.10) Abbreviations: CI, confidence interval; Hr, hour; msec, milliseconds Summary of Maximum Post-Baseline Categorical QTc Increases for Subjects Administered Moxifloxacin or Placebo on Study Day 1 Study Day 1 (PD Population) Study Day 1 (Evaluable Population) QTcF Placebomoxi (n = 48) Moxifloxacin (n = 48) Placebomoxi (n = 31) Moxifloxacin (n = 34) Maximum post-dose value 450 msec 48 (100) 38 (79) 31 (100) 27 (79) >450 msec 0 10 (21) 0 7 (21) >480 msec 0 1 (2) 0 1 (3) >500 msec Maximum change from baseline 30 msec 47 (98) 38 (79) 30 (97) 28 (82) >30 msec 1 (2) 10 (21) 1 (3) 6 (18) >60 msec 0 1 (2) 0 0 QTcB Placebomoxi (n = 48) Maximum post-dose value Moxifloxacin (n = 48) Placebomoxi (n = 31) Moxifloxacin (n = 34) 450 msec 35 (73) 21 (44) 22 (71) 17 (50) >450 msec 13 (27) 27 (56) 9 (29) 17 (50) >480 msec 0 5 (10) 0 3 (9) >500 msec 0 2 (4) 0 1 (3) Maximum change from baseline 30 msec 46 (96) 37 (77) 30 (97) 28 (82) >30 msec 2 (4) 11 (23) 1 (3) 6 (18) >60 msec 0 1 (2) 0 1 (3) Abbreviation: msec, milliseconds Summary of Maximum Post-Baseline Categorical QTc Increases on Study Day 9 for Subjects Administered or Placebo on Study Days 2 to 9 Study Day 9 Study Day 9 QTcF (n = 47) Maximum post-dose value (PD Population) (n = 44) (n = 32) (Evaluable Population) (n = 33) 450 msec 42 (89) 42 (95) 28 (88) 32 (97) >450 msec 5 (11) 2 (5) 4 (13) 1 (3) >480 msec 1 (2) >500 msec Maximum change from baseline 30 msec 46 (98) 43 (98) 32 (100) 32 (97) >30 msec 1 (2) 1 (2) 0 1 (3) >60 msec

7 QTcB (n = 47) Maximum post-dose value (n = 44) (n = 32) (n = 33) 450 msec 34 (72) 35 (80) 22 (69) 28 (85) >450 msec 13 (28) 9 (20) 10 (31) 5 (15) >480 msec 3 (6) 0 2 (6) 0 >500 msec 1 (2) Maximum change from baseline 30 msec 43 (91) 43 (98) 31 (97) 32 (97) >30 msec 4 (9) 1 (2) 1 (3) 1 (3) >60 msec Abbreviation: msec, milliseconds PK/PD Endpoints: The results of the mixed-effects modeling confirmed a significant relationship between increases in the placebo- baseline-adjusted QTcF (ddqtcf) plasma moxifloxacin concentrations demonstrating that the methods used in this study were adequate to detect small changes in the QT interval. The estimate of the slope of the ddqtcf versus plasma moxifloxacin concentration relationship was 1.82 ms/ g/ml with a stard error of The QT interval plasma pazopanib concentration data were available from a total of 46 of the 48 subjects administered pazopanib. Results of the mixed-effects modeling indicated that there was no significant relationship between the ddqtcf plasma pazopanib or pazopanib metabolite concentrations. The estimate of the slope of the ddqtcf versus plasma pazopanib concentration relationship was ms/µg/ml with a stard error of , indicating that the slope was not significantly different from zero. The estimate of the slopes (stard error) of the ddqtcf versus plasma plasma concentration relationships were (1.14), (0.837), (2.62) ms/µg/ml for the plasma pazopanib metabolites GSK , GSK , GSK , respectively. All results indicate that the slopes were not significantly different from zero. Summary of ddqtcf Values Within the Quintiles of the Plasma Moxifloxacin Concentration Range 0< 850< 1380< 1850< Plasma Moxifloxacin Concentration Range (ng/ml) < % Percentiles 75% of 50% ddqtcf 25% % Summary of ddqtcf Values Within the Quintiles of the Plasma Concentration Range Plasma Concentration Range ( g/ml) Percentiles of ddqtcf 8.09< < < < < % % % % %

8 Safety results: An on-therapy AE or SAE was defined as an AE or SAE with onset on or after the start date of study treatment but not later than 28 days after the last dose of study treatment. Three deaths were reported for the study subjects with 2 deaths reported within 28 days of the last dose of study treatment. One subject, who was assigned to moxi/placebopaz withdrawn from study after receiving a single dose of moxifloxacin on Study Day 1 due to Grade 2 tumor-related ear hemorrhage, died on Study Day 12 having received no further study treatment. This death was not considered related to study treatment by the investigator. A second subject who received placebomoxi/pazopanib died 46 days after the last dose of study treatment due to disease progression; the death was not considered related to study treatment by the investigator. A third subject, who was treated in the moxi/placebopaz treatment group, died within 28 days of the last dose of study treatment after completing treatment in this study. The subject had transitioned to the rollover study (study VEG105430) received 7 doses of pazopanib 800 mg once-daily before experiencing a fatal arrhythmia (sudden cardiac arrest leading to death) that was considered to be related to pazopanib treatment received during the rollover study by the investigator. Adverse Events (AEs) n (%) [n considered by the investigator to be related, possibly related or probably related to study treatment] AEs with Onset on Study Day 1 Placebomoxi Moxifloxacin N No. subjects with AEs n (%) 3 (6) 4 (8) Most Frequent AEs Abdominal pain lower 0 [0] 1 (2) [0] Flatulence 1 (2) [1 (2)] 0 [0] Dry mouth 0 [0] 1 (2) [1 (2)] Nausea 0 [0] 1 (2) [1 (2)] Ear hemorrhage 0 [0] 1 (2) [0] Dysgeusia 1 (2) [0] 0 [0] Epistaxis 1 (2) [0] 0 [0] Adverse Events (AEs), n (%) [n considered by the investigator to be related, possibly related or probably related to study treatment] AEs with Onset on Study Day 2 or Later N No. subjects with AEs n (%) 22 (47) 34 (71) Most Frequent AEs Fatigue 5 (11) [4 (9)] 13 (27) [13 (27)] Nausea 3 (6) [3 (6)] 12 (25) [12 (25)] Decreased appetite 1 (2) [1 (2)] 8 (17) [8 (17)] Hypertension 0 [0] 7 (15) [7 (15)] Weight decreased 0 [0] 5 (10) [5 (10)] Serious Adverse Events (SAEs), n (%) [n considered by the investigator to be related, possibly related, or probably related to study treatment]: Adverse Event (Preferred Term) (n = 47) (n = 48) Subjects with any event 2 (4) [1 (2)] 1 (2) [0] Upper gastrointestinal hemorrhage 0 [0] 1 (2) [0] Cholestasis 0 [0] 1 (2) [0] Biliary tract infection 0 [0] 1 (2) [0] Alanine aminotransferase (ALT) increased 0 [0] 1 (2) [0] Aspartate aminotransferase (AST) increased 0 [0] 1 (2) [0] Blood alkaline phosphatase increased 0 [0] 1 (2) [0] Blood bilirubin increased 0 [0] 1 (2) [0] Back pain 1 (2) [0] 0 [0] Pulmonary hemorrhage 1 (2) [1 (2)] 0 [0] Key Conclusions from Original Analysis: Moxifloxacin caused maximal QT prolongation of msec [90% CI 4.2, 17.03] at 3-hrs on Study Day 1, based on ECG measurements recorded during the 0 to 8-hr post-dose time period. The selected schedule of pazopanib administration over 8 days achieved plasma levels that were approximately 1.3 to 1.4 times higher than those previously reported for the recommended 800 mg once-daily therapeutic dose. The maximal effect of pazopanib on QTcF prolongation was 4.43 msec [90% CI -2.36, 11.22] at 8-hrs on Study Day 9, based on ECG measurements recorded during the 0 to 8-hr post-dose time period. 8

9 POST-HOC ANALYSIS: Number of Subjects: Of the 96 subjects enrolled in this study, 57 subjects were included in the 24-hr Evaluable Population for the post-hoc analysis. Summary of Analysis Populations: Disposition, n(%) (n = 47) (n = 48) Total (n = 96) No. of subjects included in PD Population (0 to 24 hrs): 47 (100) 48 (100) 96 (100) a No. of subjects included in 24-hr Evaluable Population: 28 (60) 29 (60) 57 (59) No. of subjects in the Non-24 hr Evaluable Population: 19 (40) 19 (40) 39 (41) a Not Evaluable in Original (0 to 8-hr) Analysis 15 (79) 15 (79) 31 (79) a Not Evaluable in Post-Hoc (0 to 24-hr) Analysis 4 (21) 4 (21) 8 (21) Reasons for Inevaluablility: Holter Issues 4 (100) 4 (100) 8 (100) a One subject was withdrawn from study after receiving only moxifloxacin did not receive either placebopaz or pazopanib. PD Results for 0 to 24-hrs Impact of on Heart Rate (HR): The overall trends conclusions with regards to primary secondary endpoints did not differ between the 24-hr Evaluable Population the PD Population (0 to 24 hrs); although in some cases there were numerical differences. For pazopanib-treated subjects in the PD Population (0 to 24 hrs), the baseline-adjusted, time-matched mean HR decreased (i.e., RR interval increased) compared to placebopaz for all time points on Study Day 9 with the maximum decrease in HR observed at 16-hrs post-dose followed closely by the 8-hr time point; similar impact on HR was also seen in the 24-hr Evaluable Population. Summary of Change from Baseline in HR by Treatment Group Using Repeated Measures Model (PD Population [0 to 24-hrs] 24-hr Evaluable Population) Time Points Change from Baseline on Study Day 9 (bpm) (bpm) Difference (bpm) (90% CI) PD Population (0 to 24-hrs) (N = 95) -0.5 hr (-5.72, 1.97) 1 hr (-9.65, -1.59) 2 hr (-7.95, -1.08) 3 hr (-8.97, -1.94) 4 hr (-8.76, -1.40) 6 hr (-13.31, -4.49) 8 hr (-14.17, -6.49) 12 hr (-11.70, -3.00) 16 hr (-17.18, -9.37) 20 hr (-9.82, 1.76) 24 hr (-11.57, -0.37) 24-hr Evaluable Population (N = 57) -0.5 hr (-5.40, 4.53) 1 hr (-9.72, 0.56) 2 hr (-7.87, 0.91) 3 hr (-8.49, 0.54) 4 hr (-7.20, 1.70) 6 hr (-10.89, 0.02) 8 hr (-12.29, -2.49) 12 hr (-10.82, 0.09) 16 hr (-14.85, -5.37) 20 hr (-7.60, 6.77) 24 hr (-11.40, 3.07) Abbreviation: bpm, beats per minute; CI, confidence interval; hr, hour 9

10 Impact of on PR Interval: For pazopanib-treated subjects in the PD Population (0 to 24-hrs), the maximum mean difference in the baseline-adjusted, time-matched PR interval compared to placebopaz was a decrease in the PR interval at the 20-hr post-dose time point; PR interval shortening was also seen during the 2 to 3-hr 16 to 24-hr post-dose time period while the maximum increase in the PR interval for the PD Population (0 to 24-hrs) was noted at the 8-hr post-dose time point. A similar impact on the PR interval was noted among pazopanib-treated subjects in the 24-hr Evaluable Population (i.e., maximum decrease in PR interval at the 20-hr post-dose time point), with PR interval shortening noted at all post-dose time points. Summary of Change from Baseline on PR Interval by Treatment Group Using Repeated Measures Model (PD Population [0 to 24=hrs] 24-hr Evaluable Population) Time Points Change from Baseline on Study Day 9 Difference (90% CI) PD Population (0 to 24-hrs) (N = 95) -0.5 hr (-8.95, 3.56) 1 hr (-6.10, 6.18) 2 hr (-8.66, 4.48) 3 hr (-7.86, 5.66) 4 hr (-6.23, 7.07) 6 hr (-2.98, 8.96) 8 hr (-2.22, 10.04) 12 hr (-4.12, 8.85) 16 hr (-9.50, 7.89) 20 hr (-12.79, 2.52) 24 hr (-7.44, 5.38) 24-hr Evaluable Population (N = 57) -0.5 hr (-15.78, 2.37) 1 hr (-13.05, 4.98) 2 hr (-16.23, 3.16) 3 hr (-15.70, 4.21) 4 hr (-15.52, 3.57) 6 hr (-10.57, 6.89) 8 hr (-10.71, 7.16) 12 hr (-11.52, 7.06) 16 hr (-20.39, 4.37) 20 hr (-20.26, 1.28) 24 hr (-12.89, 6.27) Abbreviation: CI, confidence interval; hr, hour; msec, milliseconds 10

11 Correcting the Effect of Changes in RR Interval on QTc: A strong positive relationship was observed for uncorrected QT RR (i.e., QT increased with increasing RR) in the PD Population (0 to 24-hrs). In view of the effect of pazopanib on HR, an analysis of QT interval using individually corrected QT interval (QTci) formula was used. QTci appears to be the more appropriate correction factor since it further decreases the dependency on RR beyond what was achieved with either QTcF or QTcB. Summary of Regression Coefficient Estimate for RR from Repeated Measures Statistical Analysis of QT, QTcF, QTcB, QTci (PD Population, N = 95) Parameter Regression Coefficient Estimate Using Baseline Data Regression Coefficient Estimate Using All Data Estimate 95% CI Estimate 95% CI QT , , QTcB , , QTcF , , QTci , , Abbreviation: CI, confidence interval Impact of on QTcF, QTcB QTci: For pazopanib-treated subjects in the 24-hr Evaluable Population, the maximum mean difference in the baseline-adjusted, time-matched QTcF interval compared to placebopaz was 4.11 msec at 24-hr post-dose on Study Day 9. The same endpoint in the PD Population (0 to 24-hrs) which includes non-evaluable subjects was 4.93 msec at 8-hrs post-dose on Study Day 9. The upper limit of the 90% CI for QTcF was above 10 msec at 8-hrs 24-hrs post-dose in the 24-hr Evaluable Population at the 20-hrs post-dose in the PD Population. Due to the unexpected variable effect of pazopanib in slowing HR, for pazopanib-treated subjects, QTcF values appear to overestimate QTcB values appear to underestimate the true effect of pazopanib on QT/QTc while individual QTci, calculated using the pre-dose RR-QT data, appear to provide the more appropriate correction of the QT interval given the effect of pazopanib on HR. For pazopanib-treated subjects in the 24-hr Evaluable Population, the maximum mean difference in baseline-adjusted, time-matched QTci interval compared to placebopaz was 0.44 (90% CI -5.94, 6.82) msec at 24-hr post-dose on Study Day 9. The same endpoint in the PD Population (0 to 24- hrs) which included non-evaluable subjects was 0.41 (90% CI -5.22, 6.03) msec at 1-hr post dose on Study Day 9. The upper limit of the 90% CI was below 10 msec for all time points for QTci in the 24-hr Evaluable Population the PD Population (0 to 24-hrs). In the 24-hr Evaluable Population, the peak effect on QTc in pazopanib-treated subjects using all 3 correction methods (QTcF, QTcB QTci) occurred at the 24-hr post-dose time point. In the PD Population (0 to 24-hrs), the peak effect on QTc in pazopanib-treated subjects was less consistent with regards to timing the magnitude of peak effect. Comparison of QT Correction Factors (QTcF, QTcB QTci): Mean Difference (90% CI) for Subjects Administered or on Study Days 2 to 9 (24-hr Evaluable Population PD Population [0 to 24-hrs]) Time Points on Study Day 9 Treatment Mean Difference (90% CI) QTcB QTcF QTci 24-hr Evaluable Population (N = 57) -0.5 hr (-6.66, 5.74) (-9.12, 4.84) (-9.03, 4.11) 1 hr 3.80 (-2.20, 9.80) (-8.75, 4.75) (-6.91, 5.86) 2 hr 0.54 (-5.45, 6.54) (-11.24, 2.25) (-9.02, 3.73) 3 hr 0.28 (-5.72, 6.27) (-12.00, 1.49) (-9.86, 2.90) 4 hr (-6.75, 5.24) (-11.57, 1.92) (-9.34, 3.44) 6 hr 3.03 (-2.96, 9.02) (-10.95, 2.53) (-8.28, 4.48) 8 hr 4.05 (-1.95, 10.05) (-11.69, 1.79) (-7.54, 5.22) 12 hr (-7.71, 4.31) (-15.32, -1.83) (-12.36, 0.42) 16 hr (-8.00, 4.07) (-21.19, -7.68) (-15.37, -2.57) 20 hr 1.51 (-4.50, 7.51) (-8.44, 5.05) (-8.23, 4.54) 24 hr 4.11 (-1.88, 10.10) (-7.11, 6.37) 0.44 (-5.94, 6.82) 11

12 PD Population (0 to 24-hrs) (N = 95) -0.5 hr 0.78 (-4.23, 5.78) (-7.63, 3.41) (-7.71, 3.86) 1 hr 3.60(-1.99, 9.20) (-7.53, 3.09) 0.41 (-5.22, 6.03) 2 hr 1.92 (-3.18, 7.01) (-8.57, 2.16) (-6.49, 4.85) 3 hr 2.76 (-2.61, 8.13) (-8.24, 2.49) (-6.37, 4.97) 4 hr 1.21 (-4.07, 6.48) (-9.04, 1.68) (-7.33, 4.00) 6 hr 4.18 (-1.28, 9.64) (-9.95, 0.77) (-7.04, 4.28) 8 hr 4.93 (-0.07, 9.94) (-10.49, 0.21) (-5.98, 5.33) 12 hr 0.90 (-4.78, 6.57) (-11.64, -0.95) (-8.67, 2.64) 16 hr 0.72 (-5.34, 6.78) (-17.49, -6.74) -6.58(-12.26, -0.90) 20 hr 3.87 (-2.31, 10.05) (-6.35, 4.53) 0.17 (-5.55, 5.89) 24 hr 4.44 (-0.94, 9.82) (-6.34, 4.54) (-6.35, 5.10) Abbreviation: CI, confidence interval; hr, hour; msec, milliseconds Categorical/Outlier Analysis of QTc Interval: On Study Day 9, no pazopanib-treated subjects in the 24-hr Evaluable Population or the PD Population (0 to 24-hrs) had a QTcF or QTcB >500 msec at any post-dose time point, whereas one placebopaz-treated subject in the PD Population (0 to 24-hrs) had a QTcB >500 msec for at least 1 postdose time point. No pazopanib-treated subjects in the 24-hr Evaluable Population or the PD Population (0 to 24-hrs) had a QTcF >480 msec at any post-dose time point on Study Day 9, whereas one placebopaz-treated subject had a QTcF >480 msec for at least 1 post-dose time point in the PD Population (0 to 24-hrs). For QTcB, 4 placebopaz-treated subjects (9%) one pazopanib-treated subject (2%) in the PD Population (0 to 24-hrs) had a QTcB >480 msec. Three subjects (11%) in the placebopaz group 1 subject (3%) in the pazopanib group had a QTcB value >480 msec for at least one time point on Study Day 9 in the 24-hr Evaluable Population Summary of Maximum Post-Baseline Categorical QTc Increases on Study Day 9 for Subjects Administered or on Study Days 2 to 9 (PD Population [0 to 24-hrs] 24-Hr Evaluable Population) Study Day 9 PD Population (0 to 24-hrs) 24-hr Evaluable Population (n = 47) (n = 46) (n = 28) (n = 29) QTcF Maximum post-dose value 450 msec 40 (85) 41 (89) 23 (82) 27 (93) >450 msec 7 (15) 5 (11) 5 (18) 2 (7) >480 msec 1 (2) >500 msec Maximum change from baseline 30 msec 44 (94) 42 (91) 28 (100) 27 (93) >30 msec 3 (6) 4 (9) 0 2 (7) >60 msec 0 1 (2) 0 0 QTcB Maximum post-dose value 450 msec 28 (60) 32 (70) 17 (61) 22 (76) >450 msec 19 (40) 14 (30) 11 (39) 7 (24) >480 msec 4 (9) 1 (2) 3 (11) 1 (3) >500 msec 1 (2) Maximum change from baseline 30 msec 40 (85) 42 (91) 25 (89) 25 (86) >30 msec 7 (15) 4 (9) 3 (11) 4 (14) >60 msec Abbreviation: hr, hour; msec, milliseconds 12

13 Holter ECGs: Holter ECG Findings: At baseline on Study Day -1, the frequency of an abnormal finding on Holter ECGs was numerically greater for pazopanib-treated subjects compared to placebopaz-treated subjects (54% vs 53%) in the PD Population (0 to 24-hrs). On Study Day 9 following administration of pazopanib or placebopaz, the frequency of an abnormal finding on Holter ECG in the 24-hr Evaluable Population the PD Population (0 to 24-hrs) was increased from baseline in placebopaz-treated subjects (57% to 71% 53% to 64%, respectively) compared to pazopanib-treated subjects (52% to 55% 54% to 52%, respectively). Holter ECG Findings for Subjects Administered or on Study Days 2 to 9 (24-hr Evaluable Population PD Population [0 to 24-hrs]) Holter ECG Findings PD Population (0 to 24-hrs) 24-hr Evaluable Population (N = 47) (N = 48) (N = 32) (N = 33) Day -1 Worst Finding n Normal 16 (34) 16 (33) 9 (32) 8 (28) Normal with Borderline 6 (13) 6 (13) 3 (11) 6 (21) Abnormality a Abnormal 25 (53) 26 (54) 16 (57) 15 (52) Unable to evaluate Day 9 Worst Finding n Normal 10 (21) 12 (26) 4 (14) 6 (21) Normal with Borderline 7 (15) 10 (22) 4 (14) 7 (24) Abnormality a Abnormal 30 (64) 24 (52) 20 (71) 16 (55) Unable to evaluate a. Borderline abnormality includes sinus bradycardia (39 bpm <HR <50 bpm), sinus tachycardia (100 bpm <HR <119 bpm), ectopic supraventricular beats, ectopic ventricular beats, low QRS voltage. Holter ECG Abnormalities: Study Day 9: In contrast to the 0 to 8-hr time period, there were no restrictions on activity level or food consumption for both pazopanib- placebopaz-treated subjects while they were wearing the Holter monitor during the 8 to 24-hr time period. Therefore, changes in HR due to varying activity levels, including sleep/wake cycle, or food consumption could not be controlled in this time period. Summary of Holter ECG Abnormalities for 2 or more Subjects Administered or on Study Days 2 to 9 (24-hr Evaluable Population PD Population [0 to 24-hrs]) Study Days 2 to 9 (24-hr Evaluable Population) Holter ECG Abnormality (n = 28) (n = 29) Day-1/Any Day 9/Any Day-1/Any Day 9/Any Measurement Measurement Measurement Measurement Any abnormality 19 (68) 24 (86) 21 (72) 23 (79) Sinus tachycardia (HR >100 bpm) 7 (25) 11 (39) 13 (45) 10 (34) Other: technical issues 3 (11) 6 (21) 7 (24) 10 (34) T waves flat 5 (18) 6 (21) 6 (21) 8 (28) Sinus bradycardia (HR <50 bpm) 3 (11) 2 (7) 3 (10) 6 (21) Ectopic supraventricular beats 5 (18) 1 (4) 5 (17) 5 (17) ST depression 5 (18) 6 (21) 3 (10) 4 (14) 1 st degree AV block 5 (18) 7 (25) 2 (7) 3 (10) (PR interval >200 msec) T-wave inversion 7 (25) 7 (25) 3 (10) 3 (10) T waves biphasic 2 (7) 2 (7) 2 (7) 2 (7) 13

14 Left anterior hemiblock 4 (14) 4 (14) 4 (14) 2 (7) Non-specific intraventricular 1 (4) 0 1 (3) 2 (7) conduction delay (QRS 120 msec) Left ventricular hypertrophy (3) 1 (3) Ectopic ventricular beats 3 (11) 2 (7) 4 (14) 1 (3) Left atrial abnormality (P mitrale) 1 (4) 1 (4) 1 (3) 1 (3) Myocardial infarction, septal (3) Other: marked bradycardia (3) Other: myocardial infarction (3) Ectopic supraventricular rhythm 1 (4) Incomplete RBBB 1 (4) RBBB 1 (4) 1 (4) 0 0 Other abnormal rhythm: PVC 1 (4) couplet Other abnormal rhythm: one (3) 0 premature junctional complex QT/QTc prolongation 500 msec 3 (11) 1 (4) 1 (3) 0 QTcB prolongation >500 msec 3 (11) 1 (4) 1 (3) 0 U waves abnormal 0 1 (4) 0 0 Low QRS voltage (3) 0 Other: Marked PR prolongation 0 2 (7) 0 0 Other: prolonged QTc 3 (11) 1 (4) 1 (3) 0 Study Days 2 to 9 (PD Population [0 to 24-hrs]) Holter ECG Abnormality (n = 48) (n = 47) Day-1/Any Day 9/Any Day-1/Any Measurement Measurement Measurement Any abnormality 31 (66) 37 (79) 32 (67) 34 (74) Sinus tachycardia (HR >100 bpm) 12 (26) 20 (43) 18 (38) 15 (33) Other: technical issues 6 (13) 9 (19) 10 (21) 13 (28) T-waves flat 12 (26) 13 (28) 9 (19) 12 (26) Sinus bradycardia (HR <50 bpm) 4 (9) 2 (4) 4 (8) 10 (22) Ectopic supraventricular beats 7 (15) 3 (6) 6 (13) 7 (15) T-wave inversion 10 (21) 10 (21) 3 (6) 5 (11) ST depression 7 (15) 8 (17) 3 (6) 5 (11) Day 9/Any Measurement First degree AV block 5 (11) 7 (15) 3 (6) 4 (9) (PR interval >200 msec) T-waves biphasic 2 (4) 4 (9) 3 (6) 4 (9) Left anterior hemiblock 5 (11) 5 (11) 5 (10) 3 (7) Non-specific intraventricular 3 (6) 1 (2) 1 (2) 2 (4) conduction delay (QRS 120 msec) Ectopic ventricular beats 4 (9) 3 (6) 5 (10) 1 (2) Left atrial abnormality (P mitrale) 1 (2) 1 (2) 1 (2) 1 (2) Left ventricular hypertrophy (2) 1 (2) Left posterior hemiblock (2) 1 (2) Incomplete RBBB 1 (2) 0 1 (2) 1 (2) Low QRS voltage (4) 1 (2) 14

15 Myocardial infarction, septal (2) Other abnormal rhythm: atrial (2) bigeminy Other: myocardial infarction (2) Other: marked bradycardia (2) Ectopic supraventricular rhythm 1 (2) U waves abnormal 0 1 (2) 0 0 Other abnormal rhythm: one (2) 0 premature junctional complex Other abnormal rhythm: PVC 1 (2) couplet Other: marked PR prolongation 0 2 (4) 0 0 QTcB prolongation >500 msec 4 (9) 2 (4) 1 (2) 0 QT/QTc prolongation 500 msec 4 (9) 2 (4) 1 (2) 0 Other: prolonged QTc 4 (9) 2 (4) 1 (2) 0 RBBB 1 (2) 1 (2) 1 (2) 0 Abbreviations: AV, atrioventricular; bpm, beats per minute; HR, heart rate; PVC, premature ventricular contraction; QTc, corrected QT interval; QTcB, Bazett s-corrected QT interval; msec, milliseconds; RBBB, right bundle branch block PK: On Study Day 9, mean plasma concentrations at 24-hrs for pazopanib all 3 metabolites were less than the mean values observed at 8-hrs post-dose. Mean plasma pazopanib, GSK , GSK decreased approximately 26%, 38%, 30%, respectively, from 8 to 24-hrs after administration of pazopanib. In contrast, mean plasma GSK concentrations declined approximately 13% over the same time period. PK/PD Relationship: Changes in HR Plasma Concentrations: Summary of Baseline-Adjusted HR (dhr) Values within the Quintiles of the Plasma Concentration Range Plasma Concentration Range ( g/ml) Percentiles of dhr (bpm) 8.09< < < < < % % % % % Abbreviation: bpm, beats per minute Mixed-Effects PK/PD Modeling Results: ddqtcf: Results of the mixed-effects modeling that included PK ECG data collected at 24-hrs indicated that there was no significant relationship between ddqtcf plasma pazopanib or its metabolite concentrations. Change from Baseline in HR: Significant relationships between change from baseline in heart rate (dhr) plasma concentrations of pazopanib the metabolite GSK were observed. Addition of plasma GSK concentrations to the model resulted in the largest decrease in the objective function relative to the base model. Addition of plasma pazopanib concentrations to the model resulted in the next largest decrease in the objective function relative to the base model. Addition of plasma pazopanib concentrations to the plasma GSK concentrations did not result in a significant decrease in the objective function or improvement of the goodness of fit plots relative to the model with plasma GSK concentrations alone. These results suggest that GSK concentrations had the most significant influence on time-matched, baseline-adjusted HR. Change from Baseline in PR: Results suggest that there is no significant concentration-effect relationship between dpr plasma pazopanib or its metabolites. Key Conclusions from Post-Hoc Analysis: The incorporation of additional Holter ECG time points between 8 24-hrs did not significantly alter any of the key conclusions from the original analyses based on Holter ECG data from 0 to 8-hrs; however, the current post-hoc analysis did identify a numerically larger decrease in HR beyond 8 hrs post-dose in pazopanib-treated subjects compared to placebopaz. 15

16 For the pazopanib-treated subjects in the PD Population (0 to 24-hrs), the maximum mean difference in the baselineadjusted, time-matched HR compared to placebopaz was a numerically larger decrease in HR ( bpm [90% CI , -9.37] at 16-hrs post-dose) compared to the original PD Population (0 to 8-hrs) where a bpm (90% CI , -5.80) decrease in HR was observed at 8-hrs post-dose. Due to the even larger effect of pazopanib in slowing HR identified in the post-hoc analysis, QTcF values appear to overestimate QTcB values appear to underestimate the true effect of pazopanib on QT/QTc, while QTci, calculated using the pre-dose RR-QT data over 24 hrs, appear to provide the more appropriate correction of the QT interval. For pazopanib-treated subjects in the 24-hr Evaluable Population, the maximum mean difference in the baselineadjusted, time-matched QTcF interval compared to placebopaz was 4.11 msec (90% CI -1.88, 10.10) at 24-hrs postdose on Study Day 9 which is similar but numerically smaller in magnitude compared to the original Evaluable Population (0 to 8-hrs) (4.43 msec [90% CI -2.36, 11.22] at 8-hrs post-dose). For pazopanib-treated subjects in the 24-hr Evaluable Population, the maximum mean difference in the baseline-adjusted, time-matched QTci interval compared to placebopaz, was 0.44 msec (90% CI -5.94, 6.82) at 24-hrs post-dose. The numerically small change in QTci value in pazopanib-treated subjects, the lack of correlation between QTcF plasma concentration of pazopanib its metabolites, the absence of any significant abnormalities identified for pazopanib-treated subjects in the QTc outlier analysis, all suggest there is no clinically significant QTc interval prolongation in pazopanib-treated subjects compared to placebopaz. For the pazopanib-treated subjects in the PD Population (0 to 24-hrs), the maximum mean difference in the baselineadjusted, time-matched PR interval compared to placebopaz was a decrease in the PR interval that was numerically larger (-5.14 msec [90% CI , 2.52] at 20-hrs post-dose) compared to the original PD Population (0 to 8-hrs) where a 3.12 msec (90% CI -4.12, 10.36) increase in PR interval was observed at 8-hrs post-dose. The small numerical increase of PR interval in pazopanib-treated subjects, the lack of correlation between PR interval plasma concentration of pazopanib its metabolites, the lack of support from the outlier analysis of the frequency of subjects with first degree AV block above baseline compared to placebopaz, all suggest that pazopanib treatment is not associated with a clinically significant PR interval prolongation. For the pazopanib-treated subjects in the PD Population (0 to 24-hrs), the ECG abnormalities noted to increase in frequency from baseline compared to placebopaz-treated subjects were generally the same as those noted in the original PD Population (0 to 8-hrs). Although not identified in the original analysis using unadjusted HR, there is a concentration-effect relationship between plasma pazopanib plasma GSK concentrations a decrease in time-matched, baselineadjusted HR over both the 8-hr 24-hr time periods. However, it is not known if the observed decrease from baseline in HR is a direct effect of exposure to pazopanib /or GSK or an indirect effect on HR caused by some other mechanism (e.g., an increase in blood pressure). 16