\\~i\)
`
`Interdisciplinary Review Team for QT Studies Consultation:
`Thorough QT Study Review
`
`NDA
`Brand Name
`Generic Name
`Sponsor
`Indication
`Dosage Form
`Drug Class.
`Therapeutic Dosing Regimen
`
`Duration of Therapeutic Use
`Maximum Tolerated Dose
`Submission Number and Date
`Clinical Division
`PDUFA GOAL DATE
`
`1 SUMMAY
`
`22-334
`
`AFINITOR
`
`Everolimus, RADOO 1
`
`Novartis
`Treatment of advanced Renal Cell Carcinoma
`
`Tablets
`
`mTOR inhibitor
`
`10 mg qd-
`
`Chronic
`
`Not determined
`
`June 27, 2008
`
`DDOP / HFD 150
`
`March 30, 2009
`
`this TQT study. The largest upper bounds of
`
`1.1 OVERALL SUMMARY OF FINDINGS
`No significant QT prolongation effect ofRADOOl (20 mg and 50 mg) was detected in
`the 2-sided 90% CI for the mean difference
`between RADOO 1 (20 mg and 50 mg) and placebo were below 10 ms, the threshold for
`regulatory concern as described in ICH E 14 gui~nce. However, the exposures achieved
`with the 50-mg dose do not cover the increase in RAOOI exposures due to CYP3A4 and
`PgP inhibition. Higher exposure could not be achieved with administering higher doses
`because ofthe less than dose proportional increases in RADOO 1 exposure. There was no
`relationship between RADOOI concentrations and QTc changes within the current
`exposure range.
`
`The TQT study (part 2) was a single-dose, randomized, blinded (RADOO 1 versus
`placebo), 4-period crossover study in 59 healthy volunteers. Overall findings are
`summarized in Table 1. The largest lower bound ofthe two-sided 90% CI for the
`b.b.QTcF for moxif1oxacin was greater than 5 ms, and the moxif1oxacin profie over time
`is adequately demonstrated in Figure 4, indicating that the assay sensitivity ofthe study
`was established.
`
`

`

`Table 1: The Point Estimates and the 90% CIs Corresponding to the Largest Upper
`Bounds for RA001 (20 mg and 50 mg) and the Largest Lower Bounds for
`Moxifloxacin (FDA Analysis)
`Treatment
`Time (h)
`ililQTcF
`RAD00120 mg
`12h
`3.7
`RADOOI 50 mg
`4.7
`12h
`(2.5,6.8)
`Moxif1oxacin 400 mg*
`4h
`12.8
`(10.9, 14.6)
`* Multiple endpoint adjustment is not applied. The largest lower bound after Bonferrorii adjustment
`was 9.84 ms.
`
`90%CI
`
`( 1.6, 5.9 )
`
`1.2 QT INTERDISCIPLINARY REVIEW TEAM'S COMMENTS
`
`RADOOI 50 mg was selected as the supratherapeutic dose in part 1 of
`
`the study. This
`dose is not the maximum tolerated dose because there were no dose-limiting toxicities.
`Administering doses higher than 50 mg would not increase the exposure to RADOO 1
`. because it pharmacokinetics are less than dose proportionaL. The mean Cmax achieved
`with RADOOI 50 mg (160:: 40 ng/ml, BSV = 25%) is approximately twice the mean
`Cmax achieved after administering 10 mg qd to steady state (77 :: 39 nglml, BSV=51 %).
`The RADOOI doses evaluated (20 mg and 50 mg QD) in this study do not cover the
`expected increases in exposures due to metabolic inhibition with moderate and potent
`moderate CYP3A4 and PgP inhibitors
`(erythromycin, verapamil) increased mean Cmax by two-fold. Moreover, there was a 4-
`and 15-fold increase in Cmax and AUC when RADOOI was coadministered with potent
`strong inhibitors is not
`contraindicated in the proposed package insert; however, the sponsor does recommend
`that coadministration with strong inhibitors or inducers ofCYP3A4 or PgP should be
`avoided where possible (see Drug Interactions).
`In subjects with moderate hepatic impairment, the mean AUC value is doubled but there
`was no change in mean Cmax. The sponsor recommends dose reduction to 5 mg daily in
`patients with Child-Pugh class B. RADOO 1 is not recommended in patients with Child-
`Pugh class C hepatic impairment.
`
`CYP3A4 and PgP inhibitors. Coadministration of
`
`CYP3A4 and PgP inhibitors (ketoconazole). The use of
`
`2 PROPOSED LABEL
`The sponsor did not include a description of study results in the proposed labeL. The
`. following text is our suggestions for labeling. We defer all labeling decisions to the
`clinical review team.
`
`12.2 Pharmacodynamics
`
`r-
`
`\)\4)
`
`-l
`
`2
`
`

`

`3 BACKGROUND
`Everolimus is a derivative of rapamycin and acts as a signal transduction inhibitor. Its
`target is mTOR, a key regulatory serine-threonine kinase regulating metabolism, cell
`growth and proliferation, and angiogenesis. This submission by the sponsor is to obtain
`approval for everolimus 10 mg daily for the treatment of patients with advanced renal cell
`carcinoma.
`
`3.1 MARKET APPROVAL STATUS
`Everolimus (Certican(ß) is commercially available within the European Union and other
`markets for the prophylaxis of allograft rejection following renal or cardiac
`transplantation, in conjunction with cyclosporine and glucocorticoid therapy. The first
`marketing approval was received in June 2003 from the Swedish Health Authority.
`Overall, :;3000 transplant patients have received treatment with everolimus in Novartis-
`sponsored studies; doses administered in this setting (where the initial dosage
`recommendation is 1.5 mglday) are lower than those proposed for the oncology patient
`population (10 mg/day).
`
`3.2 PRECLINICAL INFORMATION
`Source: Pharrmacology Written Summary, 31-March 2008 (CTD 2.6.2)
`
`"RADOOI at a target concentration of 10 ¡.M (9.6 ¡.g1ml; corrected values: 304 ¡.M
`and 3.3 ¡.g/ml) and of16 ¡.M (15.3 ¡.g/ml; corrected values: 9.7 ¡.M and 9.3
`¡.g/ml) inhibited hERG channel activity in stably transfected HEK293 cells by 2.6
`and 17.5 %, respectively. (Report 0710800)
`
`"RADOOI had no influence on QT interval prolongation (TPCH_ 98-062_Expert).
`Effects ofRADOOl at concentrations of 100, 1000 or 10000 ng/ml, corresponding
`to 0.104, 1.04 or lOA ¡.M, were assessed on intra-cellularly recorded action
`potential parameters in the sheep isolated cardiac Purkinje fibre preparation
`electrically paced at 1 Hz.
`
`RADOO 1 had no effect on the Purkinje fibre action potential duration, amplitude
`or maximum rate of depolarization. The diastolic membrane potential recorded in
`these fibres was also unaffected. These data indicate that plasma concentrations
`up to 10000 ng/mL are unlikely to have effects on ECG parameters.
`"The re-evaluation of electrocardiograms in the 2-week, 4-week and 26-week oral
`toxicity studies with RADOO 1 in cynomolgus monkeys did not indicate any test
`article-related changes. In a 4-week oral combination study with cyclosporin A,
`the compounds. The
`increased QT interval in one animal treated with the cyclosporin AlDOO 1
`combination at 100/0.25 mglkg, recorded before early necropsy, was associated
`with a decrease in heart rate. This was considered to be related to electrolyte
`disturbances secondary to dehydration and poor health status. The
`electrocardiographic recordings in minipigs after intravenous infusion ofRADOOl
`showed no potential for QT interval prolongation."
`
`there were no changes attributable to a direct effect of
`
`3
`
`

`

`Source: Summary of
`
`3.3 PREVIOUS CLINICAL EXPERIENCE
`Clinical Safety, 22 May 2008, CTD -2.7.4
`"This safety evaluation of everolimus 10 mg daily, administered as monotherapy,
`is based upon data from 596 patients from the clinical development program.
`Data from a further 432 subjects (350 patients and 82 healthy volunteers) from
`completed studies also contribute to this evaluation
`"2.1.2.1 Deaths in double-blind phase of pivotal phase-II trial (Study C2240)
`Deaths 'on-treatment' (i.e., while receiving study medication or within the initial
`28 days of discontinuing therapy) were recorded for 20 patients (5.0%) by the
`data cut-off date of 15-0ct-2007. Eighteen ofthese 20 deaths (90.0%) were
`attributed to the underlying malignancy (this includes the acute renal failure case
`(Patient 0758-00004)) while the remaining two were from solitary events. One
`patient ((Patient 609-00003)) treated with everolimus died from overwhelming
`candidal sepsis, complicated by acute respiratory failure, and which may have
`been attributable to the study drug. The second patient ((Patient 753-00002)), who
`was initially treated with placebo, died as the result of a myocardial infarct 3 days
`after commencing treatment with open-label everolimus.
`"2.1.2.2 Deaths in pooled dataset (monotherapy safety population)
`Across the broader development program reported in the pooled dataset, 6
`patients (1.0%) have died where the primary cause of death was reported to be an
`AE within the 'respiratory, thoracic, and mediastinal disorders' system organ
`class. Review ofthe individual cases identified two deaths (reported as acute
`respiratory distress syndrome and respiratory failure, respectively) that were
`related to ARDS in the context of infection (Pneumocystis carinii pneumonia in
`one case and 'candidal pneumonia and sepsis' in the second. No common
`etiology was shared in the remaining four cases; these were due to progressive
`lung cancer (report of acute pulmonary edema), esophageal perforation (report of
`vomit (report of aspiration), and progressive
`respiratory failure).
`"ECGs were not routinely performed or analyzed in the phase-I, -II, or-II
`studies, although where these results were available, no significant mean changes
`from baseline QTc were evident. No patient receiving everolimus experienced a
`treatment-emergent QTc interval :;500 ms or had ventricular tachycardia."
`Reviewer's Comments: There are no reports of AEs related to QT prolongation (i.e.)
`sudden cardiac death, syncope, seizure or signifcant ventricular arrhythmias.
`
`hydropneumothorax), aspiration of
`
`renal cancer (report of
`
`3.4 CLINICAL PHARMACOLOGY
`Appendix 6.1 summarizes the key features ofRADOOl's clinical pharmacology.
`
`4
`
`

`

`4 SPONSOR'S SUBMISSION
`
`4.1 OVERVIEW
`The sponsor submitted the study report for CRADOO 1 C2118, including electronic
`datasets and waveforms to the ECG warehouse.
`
`4.2 TQT STUDY
`
`4.2.1 Title
`A blinded, randomized, placebo and active controlled, single-dose crossover study to
`investigate the effect ofRADOOl on cardiac intervals in healthy volunteers.
`
`4.2.2 Protocol Number
`CRADOOIC2118
`
`4.2.3 Study Dates
`11 July 2007 to 19 November 2007
`
`4.2.4 Objectives
`The primary objective is to assess the effect of a single dose, on heart rate and cardiac
`conduction intervals (QT, QTc, QTcB, QTcI, QRS, RR, and PR) in adult healthy
`volunteers.
`
`4.2.5 Study Description
`
`4.2.5.1 Design
`The study was carried out in two phases.
`Part 1 was a dose finding pilot phase. The following doses were investigated to find the
`supra-therapeutic dose to be used in Part 2: RADOOI 20 mg, RADOOI 30 mg, and
`RADOOI 50 mg.
`Part 2 was the thorough QT/QTc study designed as a single-dose, randomized, blinded
`(RADOOI versus placebo), 4-period crossover study with active (moxifioxacin, open-
`label) and negative (placebo) control to assess the effect ofRADOOl at a therapeutic (20
`mg) and supratherapeutic dose (50 mg) on cardiac conduction and repolarization. A total
`of 60 subjects were planned for this part.
`
`4.2.5.2 Controls
`The Sponsor used both placebo and positive (moxifioxacin) controls.
`
`4.2.5.3 Blinding
`The administration ofRADOOl and placebo was double-blinded. Moxifioxacin was
`administered open labeL.
`
`5
`
`

`

`4.2.6 Treatment Regimen
`
`4.2.6.1 Treatment Arms (Part 2)
`Treatments No. ofRADOOl tablets or matching placebo tablets as single dose
`20 mg 4 tablets ofRADOOl 5 mg and 6 matching placebo tablets
`50 mg 10 tablets ofRADOOl 5 mg (supra-therapeutic dose)
`Placebo 10 matching placebo tablets
`Moxifloxacin 1 tablet of 400 mg moxifloxacin
`
`All doses were administered under fasting conditions together with 200 mL of
`
`were to be swallowed within 3 minutes.
`
`water and
`
`4.2.6.2 Sponsor's Justifcation for Doses
`"Part 1 was a dose finding pilot phase. The following doses were investigated to
`find the supra-therapeutic dose to be used in Part 2: RADOOI 20 mg, RAOOI 30
`mg, and RADOO 1 50 mg. The following procedure was performed, to determine
`the supra-therapeutic dose:
`
`· If
`
`Dose Limiting Toxicity (DLT) / drug related AEs of
`
`Common Toxicity
`Criteria (CTC) equal or greater than grade 3 unexpectedly would occur in
`the 50 mg cohort the dose level was to be reduced to 30 mg and became
`the clinical study.
`· IfDLT / drug related AEs ofCTC equal or greater than grade 3
`unexpectedly would occur in the 30 mg cohort, Part 2 was to be conducted
`without a supra-therapeutic dose.
`
`the supra-therapeutic dose for the second part of
`
`· IfDLT / drug related AEs ofCTC equal or greater than grade 3
`the clinical study
`
`unexpectedly would occur in the 20 mg cohort, Part 2 of
`
`"The duration of
`
`was not to be conducted.
`evaluation ofDLT or drug related AEs was up to 14 days after
`dosing. According to the safety results of Part 1: no drug-related AEs of CTC
`grade 3 or greater in the 50 mg cohort, the supra-therapeutic dose was identified
`as 50 mg."
`
`Reviewer's Comments: Sponsor's choice of
`
`not cover high exposures possible with coadministration of
`
`therapeutic and supratherapeutic doses did
`potent CYP3A4 and PgP
`inhibitors. There were no dose limiting toxicities observed in part 1 so 50 mg QD is not
`the MTD. However, since the increase in Cmax beyond 10 mg single dose was less than
`dose proportional, increase in doses over 50 mg would not have helped increase the
`exposure.
`
`Since RADOOl is primarily eliminated by liver, there are two possible worst case
`scenarios (hepatic impairment and coadministration ofCYP3A4 inhibitors) that are
`likely to increase its exposure. Moderate hepatic impairment doubles the A UC while
`there is no change in Cmax. Sponsor recommends reduction of dose to 5 mg daily in these
`
`6
`
`

`

`patients. RAD001 has not been studied in severe hepatic impaired subjects and thus its
`use is not recommended in this population.
`
`Coadministration of
`
`with coadministration of
`
`dose. However, concomitant use of
`
`moderate inhibitors ofCYP3A4 increases the Cmax by 2-fold, which
`is likely to be covered by the exposures achieved by supratherapeutic dose (50 mg). But,
`strong CYP3A4 inhibitors (Ketoconazole) the Cmax andAUC is
`increased by 4 and 15-fold, respectively which is not covered by the supratherapeutic
`strong CYP3A4 inhibitors is to be avoided (not
`contraindicated), as stated in the labeL. Even though there was a moderate accumulation
`first dose and
`at steady state were similar and exhibited high intersubject variabilty (40-50%).
`
`(accumulationfactor=1. 7) for RAD001 after 10 mg daily dose, the Cmax at
`
`4.2.6.3 Instructions with Regard to Meals
`
`All doses were administered under fasting conditions together with 200 mL of
`
`were to be swallowed within 3 minutes.
`Reviewer's Comments: It is acceptable as per the information provided in the labeL.
`
`water and
`
`4.2.6.4 ECG and PK Assessments
`
`Study Day
`
`Intervention
`
`12- Lead ECGs
`
`PK Samples for
`drug
`
`-1
`
`1
`
`No treatment (Baseline)
`
`20 or 50 mg single dose
`
`Pre-dose (0 h) and 0.5, 1, 1.5,
`2, 3,4, 8, 12 and 23.5 h
`
`None collected
`
`0.5, 1, 1.5,2,3,4,8, 12 and 23.5 h
`
`Pre-dose (-5 min), 0.5, 1, 1.5,2,
`3,4, 8, 12 and 23.5 h
`
`Two kinds of
`
`4.2.6.5 Baseline
`baseline have been derived.
`· Time average baseline: The baseline for post-dose measures at all time points is
`the mean of all time point measurements at Day -1.
`
`· Time match baseline: The baseline for a post-dose measure is the measure at the
`same time point in Day -1.
`Day -1 was the day immediately before first intake of study medication. The hypothesis
`tests used the time average baseline.
`
`4.2.7 ECG Collection
`In Part 2, continuous 12-1ead ECGs were recorded using a 12-1ead Digital Holter
`recorder. The subject was resting quietly in the supine position for at least 10 minutes
`before each triplicate scheduled ECG assessments on Day 1 for each period.
`
`7
`
`

`

`The ECG waveforms were recorded on the compact flash memory cards (flash cards)
`provided to the study site. Triplicate ECG (7.5 sec, 12 lead) assessments were extracted b~4)
`by the central lab - at the time points specified in section 4.2.6.4.
`
`Interval duration measurements were made from 3 waveforms, typically using Lead II. A
`standard digital 12-1ead ECG was recorded during the treatment period ifthere were any
`safety concerns.
`
`4.2.8 Sponsor's Results
`
`4.2.8.1 Study Subjects
`Healthy adult male (34) and female (30) subjects, 18-65 yrs of age with a normal baseline
`ECG and BMI 20-32 kg/m2 were included.
`In Part 1, 24 subjects were randomized. All 24 subjects completed the clinical study
`according to the protocol.
`In Part 2, 64 subjects were randomized. Five subjects were withdrawn from the clinical
`abnormal test procedure result, and
`Subject 20008 withdrew consent. In total, 59 subjects completed the clinical study as per
`protocol.
`
`study-3 because of AEs, Subject 20016 because of
`
`4.2.8.2 Statistical Analyses
`
`4.2.8.2.1 Primary Analysis
`The change from baseline QTcF was analyzed using a linear mixed effects model fitting
`terms for sequence, treatment, period, time and treatment-by-time interaction, where
`in-sequence was treated as a random effect. Baseline QTcF was included as a
`covariate in the modeL. Point estimates and 95% CIs (one-sided) were generated at each
`point for treatment difference (active-placebo). Results are provided in Table 2, Table 3
`and Table 4 below.
`
`subject-with
`
`Day
`
`1
`
`Table 2: SDonsor's ~QTcF Analysis: RAD001 20m2 vs. Placebo
`Treatment Difference: ddQTcF
`Time
`Estimate
`90% Confidence Interval
`S.E.
`-0.58
`0.5h post-dose
`1.10
`-0.16
`1 h post -dose
`1.10
`0.72
`1.5h post-dose
`1.10
`2h post-dose
`1.60
`1.10
`3h post-dose
`0.56
`1.10
`1.60
`1.10
`4h post-dose
`2.26
`8h post-dose
`1.10
`12h post-dose
`4.15
`1.11
`23.5h post-dose
`3.36
`1.11
`Source: Table 16.1-9.1.b (page 1429) and Table 16.1-9.11b (page 1430)
`
`(-2.39, 1.23)
`
`(-1.97, 1.65)
`(-1.09,2.53)
`(-0.21,3.41)
`(-1.26, 2.37)
`(-0.21,3.41)
`( 0.45, 4.08)
`( 2.33, 5.97)
`( 1.55,5.18)
`
`8
`
`

`

`Day
`
`1
`
`, i1QT FA I . RA00150
`a
`: ~ponsor s
`naiysis:
`PI b
`mgvs.
`e
`T bl 3 S
`c
`ace 0
`Treatment Difference: ddQTcF
`Time
`Estimate
`S.E.
`90% Confidence Interval
`0.5h post-dose
`-1.32
`1.10
`(-3.14,0.49)
`Ih post-dose
`-0.48
`1.10
`(-2.29, 1.34)
`-0.40
`1.5h post-dose
`1.10
`0.35
`1.10
`2h post-dose
`3h post-dose
`0.90
`1.10
`0.84
`1.10
`4h post-dose
`8h post-dose
`3.09
`1.10
`12h post-dose
`4.26
`1.10
`23.5h post-dose
`3.46
`1.11
`Source: Table 16.1-9.1.b (page 1429) and Table 16.1-9.11b (page 1430)
`
`(-2.21, 1.42)
`(-1.47,2.16)
`(-0.91,2.71)
`(-0.97,2.66)
`( 1.27, 4.90)
`( 2.45, 6.07)
`( 1.63, 5.29) .
`
`Day
`
`1
`
`, i1QT F A I . M 11
`a
`: ~ponsor s
`naiysis:
`e
`PI b
`T bl 4 S
`c
`ace 0
`oxl oxacin vs.
`Treatment Difference: ddQTcF
`Time
`Estimate
`S.E.
`90% Confidence Interval
`0.5h post-dose
`9.22
`1.11
`1 h post -dose
`10.95
`1.11
`1.5h post-dose
`11.12
`1.11
`13.01
`1.11
`2h post-dose
`3 h post-dose
`12.55
`1.11
`13.08
`1.11
`4h post-dose
`8h post-dose
`9.92
`1.11
`12h post-dose
`9.93
`1.11
`23.5h post-dose
`4.77
`1.11
`Source: Table 16.1-9.1.1 b (page 1429) and Table 16.1-9.11 b (page 1430)
`
`(7.41, 11.03)
`
`(9.13, 12.77)
`
`(9.31, 12.93)
`
`(11.20, 14.82)
`
`(10.74, 14.36)
`
`(11.27, 14.90)
`( 8.10, 11.74)
`(8.11,11.74)
`( 2.96, 6.59)
`
`4.2.8.2.2 Categorical Analysis
`
`The Sponsor reported that none of
`
`the subjects had their change from baseline QTcF over
`59 (5%) subjects had their QT over 450 ms.
`However, none ofthe subjects had their QTcF over 450 ms.
`
`30 ms. The Sponsor reported that 3 out of
`
`4.2.8.3 Safety Analysis
`There were no deaths or SAEs in this study.
`Three subjects discontinued due to AEs. Subject 20027 discontinued due to nausea and
`vomiting after receiving 50mg RADOO 1. Subject 20029 discontinued after developing a
`maculopapular rash and pruritis after receiving moxifloxacin. Subject 20120 developed
`stomatitis after receiving moxifloxacin and 50 mg RADOO 1.
`
`9
`
`

`

`4.2.8.4 Clinical Pharmacology
`
`A summary of
`
`4.2.8.4.1 Pharmacokinetic Analysis
`the main PK parameters ofRADOOl are presented in Table 5. Mean
`1 from Part 1 are
`
`concentration-time profile plots after 20,30 and 50 mg of
`
`shown in Figure 1.
`
`RADOO
`
`Figure 1: Mean blood concentrations ofRAOOl after
`single oral doses of 20, 30 and 50 mg -Part 1
`
`l(,\i \'
`
`i ".'
`i \~
`
`61\\". \
`". \\\\.".~ ..
`
`6.... '"
`
`.........::~.-:.-:.:'.;:.::::.-::-::.-:.:::::::.-:.-:.::.:-.::::;::.-:.:.::ó
`
`o
`
`o
`
`5
`
`10
`
`15
`
`20
`
`25
`
`Source: c2118 report, Figure 11-5
`
`Time (h)
`
`Table 5: Main pharmacokinetic parameters ofRAOOl in blood after single oral
`doses of20 mg or 50 mg in healthy volunteers-Part 2.
`Dose (mg) T max (hI Cm.x (nglmL) AUCO-tlast (h.ng/mL)
`20 (N = 61) 0.5 (0.5 - 2.0) 109.43 (25.31) 542.1 (149.2)
`50 (N = 61) 0.5 (0.5 - 1.5) 159.71 (39.51) 1022.8275.4)
`Values are mean (SD) except for T max, which is median (range).
`AUe = Area under the curve; SD = Standard deviation
`Source: c2118 report, Table 11-13
`
`Reviewer's Comments: The Cmax andAUC ofRAD001 50 mg was 1.5 and 1.9-fold of
`
`the
`therapeutic dose (20 mg). However, the proposed dosing regimenfor RAD001 is 10 mg
`daily and the Cmax achieved with the 50-mg single dose is about twice the Cmax (76.7::39.3
`ng/ml, BSV=51%) achieved at steady state with 10 mg daily regimen (Summary Clin
`Pharm, Appendix 6.1). The increase in Cmaxwas less than dose proportional after 10 mg
`single dose.
`
`Exposure-Response Analysis
`Sponsor conducted exposure response analysis to graphically explore QTcF change from
`baseline against RADOOI concentrations and found no noticeable trends.
`
`10
`
`

`

`Figure 2: Concentration vs QTcF for (a) 20 and (b) 50 mg RAOOl showing lack of
`evidence of exposure-response.
`(a)
`
`.1.
`M ,A"'.
`.+.
`'I....
`....
`2.
`--- ll mo
`8
`
`ww *
`+ + +
`
`xl( X
`
`1
`3
`12
`
`1.5
`4
`23.5
`
`50 Trn på (Ill)
`
`40
`
`I æ
`
`20
`
`10
`
`0
`
`-10
`
`-20
`
`~
`j
`!
`f -æ
`
`-40
`
`-____111..-----------
`i
`.l - . ---------
`
`..
`
`-50
`
`0
`
`60
`
`10
`
`Source: C2118 report, Pg 387
`
`100
`CCfliliitiall (~
`
`(b)
`
`3.
`
`2G
`
`30
`
`.1.
`'I"'.
`....
`--- ll mo
`
`o.s
`2.
`6
`
`.....
`.+.
`
`3 + + + 4
`1 *.. tr 1.5
`12 XX X 23.5
`
`.l'* II II
`~J_~__ II
`i ~ II :-il----------
`
`* II
`
`50 1l på (hI)
`
`40
`
`æ
`
`20
`
`10
`
`0
`
`I
`~
`l
`! -10
`l -30
`
`-20
`
`-40
`
`-60
`
`o
`
`60
`
`10
`
`160Co (ng
`
`3.
`
`2G
`
`30
`
`Source: C2118 report, Pg 388
`
`11
`
`

`

`Reviewer's Comments: The sponsor explored the correlation between concentration and
`
`Ll QTcF without adjusting
`
`for placebo. The reviewer performed the concentration-
`response analysis usingLlLlQTcF (Figure 5).
`
`5 REVIEWERS' ASSESSMENT
`
`5.1 EVALUATION OF THE QTIR CORRCTION METHOD
`The observed QT-RR interval relationship is presented in together with the Bazett's
`(QTcB), Fridericia (QTcF), and individual correction (QTcI). QTcF was used for further
`analysis.
`Figure 3: QT, QTcB, QTcF, and QTcI vs. RR (Each Subject's Data Points are
`Connected with a Line)
`
`I
`
`I
`
`600 800
`
`v
`
`.
`
`. .
`
`íi
`E--
`ro
`ì:2i:
`¡: 450a
`
`400
`
`350
`
`-
`
`1200
`
`1600
`
`i
`
`450
`
`400
`
`350
`
`/
`
`J
`
`bl4)
`
`-
`
`J
`
`r
`/~
`/
`r
`- /~
`
`T
`
`600 800
`
`5.2 STATISTICAL ASSESSMENTS
`
`T
`
`T
`1200
`
`I
`
`1600
`
`RR interval (ms)
`
`5.2.1 QTc Analysis
`The reviewer analyzed the Sponsor's SAS data provided in qtpk.xpt using a linear modeL.
`The objective was to demonstrate no QT effectofRADOOl compared to placebo. Lack of
`the upper bound of95% one-sided CI for RADI00-
`placebo was less than 10 ms for all time points. The change from baseline in QTcF at
`each time point was the primary endpoint. The RADOO 1 (20 mg and 50 mg) was
`compared with placebo. The primary analysis was performed on all time points using
`analysis of covariance model, including sequence, treatment, period, and subject, where
`
`QT effect was to be concluded if
`
`12
`
`

`

`subject-within-sequence was treated as a random effect. The moxifioxacin 400 mg was
`also compared with placebo using the same modeL. Point estimates and one-sided 95%
`CIs were generated at each time point for treatment differences (active -placebo).
`As seen from Table 6 and Table 7, the upper bounds ofthe 90% confidence interval for
`the mean difference in QTcF change from baseline between RAOOI (20 mg and 50 mg)
`and placebo were below 10 ms at all time points, which demonstrates that this is a
`negative TQT study using the proposed dose.
`As seen from Tabié 8, the largest lower 90% CI for the baseline adjusted mean difference
`of 400 mg moxifioxacin and placebo is 10.88 ms at hours 4 after dosing without multiple
`endpoint adjustment. IfBonferroni multiple endpoint correction method is applied
`(corrected for 9 time pints), the largest lower bound of ddQTcF between moxifioxacin
`and placebo is 9.83 ms. Since Bonferroni correction is the most conservative approach by
`assuming the independence of the data, we believe that assay sensitivity of the study has
`been established and this is further confirmed by the shape ofmoxifioxacin in Figure 4.
`a
`: ummaryo
`e
`T bl 6 S
`Time-
`Hour*
`0.5
`
`Day
`
`mgversus
`PI b (C B)
`na ysis:
`c
`f AQT F A I . RADOOI 20
`vs.
`ace 0
`Mean LlQTcF
`Treatment Difference: LlLlQTcF
`TRT:C
`TRT:B
`Estimate
`90%CI
`S.E.
`-4.85
`-3.67
`-1.19
`1.09
`(-2.98,0.61)
`-3.79
`-2.98
`-0.81
`1.05
`(-2.55, 0.93)
`-2.65
`-2.68
`0.04
`1.09
`1.2
`-1.55
`-2.58
`1.03
`-3.41
`-3.41
`0.00
`1.04
`-2.23
`1.4
`-3.30
`1.07
`-4.67
`1.7
`-6.46
`1.79
`1.0
`-0.58
`3.15
`3.73
`-1.02
`1.69
`2.71
`1.08
`
`(-1.77, 1.84)
`(-0.81,2.88)
`(-1.72, 1.73)
`(-0.81,2.95)
`(-0.14,3.72)
`
`( 1.59, 5.87 )
`( 0.93, 4.49 )
`
`1
`
`1
`1.5
`2
`3
`4
`8
`12
`23.5
`
`* Post-dose
`Table 7: Summar' of AQTcF Analysis: RAOOI 50 ml! versus Placebo (D vs. B)
`Time-
`Treatment Difference: LlLlQTcF
`Estimate
`90%CI
`S.E.
`-1.02
`1.09
`(-2.82,0.77)
`-0.16
`1.05
`(-1.90, 1.58)
`-0.12
`1.09
`1.2
`0.71
`1.23
`1.04
`1.8
`1.4
`1.7
`3.53
`4.68
`1.29
`3.80
`1.09
`
`Mean
`
`LlQTcF
`
`TRT:D TRT:B
`-4.69
`-3.67
`-3.15
`-2.98
`-2.80
`-2.68
`-1.87
`-2.58
`-2.18
`-3.41
`-2.12
`-3.30
`-2.93
`-6.46
`-0.58
`4.10
`-1.02
`2.78
`
`(-1.93, 1.69)
`(-1.14,2.56)
`(-0.50,2.95)
`(-0.70,3.06)
`
`( 1.60, 5.46 )
`(2.54,6.81 )
`( 2.00, 5.60 )
`
`Day
`
`Hour
`
`*
`
`0.5
`
`1
`
`1
`1.5
`2
`3
`4
`8
`12
`23.5
`
`* Post-dose
`
`13
`
`

`

`Table 8: Summary 0
`Time-
`Hour*
`0.5
`
`Day
`
`f AQTcF Analysis: Moxifloxacin versus Placebo (A vs. B)
`ßQTcF Treatment Difference: ßßQTcF
`TRT: A TRT: B Estimate S.E. 90% CI
`5.20 -3.67 8.87 1.08 ( 7.08, 10.66)
`7.71 -2.98 10.69 1.06 (8.94, 12.43)
`8.09 -2.68 10.78 1.09 ,( 8.97, 12.58)
`10.14 -2.58 12.71 1.2 (10.87,14.56)
`8.81 -3.41 12.22 1.04 (10.50, 13.94)
`9.46 -3.30 12.76 1.4 (10.88, 14.64)
`3.12 -6.46 9.58 1.7 (7.65,11.52)
`9.09 -0.58 9.67 1.29 (7.54, 11.80)
`3.58 -1.02 4.60 1.08 (2.81,6.38)
`
`11
`
`.
`
`2 3 4 8 1
`
`2
`23.5
`
`1
`
`* Post-dose
`
`The time course of ßßQTcF for the study drug RAD001 and moxifioxacin is displayed in
`Figure 4.
`
`Figure 4: ßßQTcF for RADOOl and Moxifoxacin
`
`15
`
`10
`
`5
`
`o
`
`-5
`
`dd Q T ç F
`
`o
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`14
`
`16
`
`18
`
`20
`
`22
`
`24
`
`limeqiour)
`Trt Vs. Placebo - MOXI 400 mg ~ RI'OOOI 20 mg .. RI'OOOI 50 mg
`
`14
`
`

`

`5.2.2 5.2.2 Categorical analysis
`fifty-nine (-:4%) subjects had their i1QTcF over 30 ms. Details are provided
`
`Two out of
`
`in Table 9.
`
`a
`e
`T bl 9 Ab
`:
`Treatment
`Subject ID
`Placebo
`0101 20022
`Moxifioxacin
`0101 20118
`All subjects had their QTcF below 450 ms.
`
`b l QT F
`norma c an2e rom ase me
`f
`c
`I h
`Day
`Time
`0.5h
`1
`2h
`
`1
`
`i1QTcF
`
`b(4)
`
`5.2.3 PR Analysis
`The change from baseline in PR at each time point was analyzed. The RADOOI (20 mg
`and 50 mg) was compared with placebo. The analysis was performed on all time points
`using analysis of covariance model, inCluding sequence, treatment, period, and subject,
`where subject-within-sequence was treated as a random effect. The results are
`summarized in Table 10 and Table 11.
`Table 10: Summary of APR Analysis: RA00120 m2 versus Placebo (C vs. B)
`Meani1PR
`Time-
`Treatment Difference: i1i1PR
`TRT:C
`TRT:B
`90%CI
`Estimate
`Hour*
`S.E.
`0.67
`0.60
`0.07
`0.89
`0.5
`(-0.86,2.07)
`-0.1 I
`0.89
`1.64
`1.75
`( 0.27, 3.22)
`l.5
`-0.40
`0.75
`0.89
`(-1.87,1.08)
`0.72
`0.05
`0.66
`0.88
`(-0.79,2.11)
`-1.59
`0.01
`0.95
`1.60
`( 0.03, 3. I 7)
`-1.06
`0.50
`0.95
`1.56
`(-0.01,3.12)
`-2.12
`-1.07
`1.06
`0.91
`(-0.45,2.56)
`-0.10
`-1.03
`0.93
`1.02
`(-0.76,2.61)
`-l.2
`0.86
`0.98
`1.98
`(-2.73,0.50)
`
`Day
`
`1
`
`1
`1.5
`2
`3
`4
`8
`12
`23.5
`
`* Post-dose
`
`Day
`
`1
`
`Table 11: Summary of APR Analysis: RA00150 m2 versus Placebo (D vs. B)
`Time-
`Treatment Difference: àl1PR
`Mean i1PR
`TRT:D TRT:B
`90%CI
`Estimate
`Hour
`S.E.
`0.07
`0.85
`0.89
`0.5
`0.78
`(-0.68,2.25)
`-0.11
`0.86
`0.89
`0.75
`(-0.61,2.34)
`l.5
`-0.93
`0.22
`0.89
`(-2.41, 0.55)
`0.78
`0.05
`0.88
`0.73
`(-0.72,2.18)
`-1.59
`-0.36
`0.95
`1.23
`(-0.34,2.80)
`-1.06
`-0.47
`0.58
`0.95
`(-0.98,2.15)
`-2.72
`-2.12
`-0.60
`0.92
`(-0.45,2.56)
`-1.09
`-1.03
`-0.06
`1.02
`(-1.74,1.62)
`-1.04
`0.93
`0.98
`1.98
`(-2.67,0.58)
`
`1
`1.5
`2
`3
`4
`8
`12
`23.5
`
`* Post-dose
`
`15
`
`

`

`5.2.4 QRS Analysis
`The change from baseline in QRS at each time point was analyzed. The RADOO 1 (20 mg
`and 50 mg) was compared with placebo. The analysis was performed on all time points
`using analysis of covariance model, including sequence, treatment, period, and subject,
`where subject-within-sequence was treated as a random effect. The results are
`summarized in Table 12 and Table 13 below. Single oral doses ofRADOOl 20 and 50 mg
`had no clinically relevant effect on QRS.
`Table 12: Summa ry of AQRS Analysis: RAD001 20 me versus Placebo (C vs. B)
`Time-
`Mean~QRS
`Treatment Difference: ~~QRS
`TRT:C
`TRT:B
`Hour
`Estimate
`90%CI
`S.E.
`O.p
`-0.66
`0.5
`-0.83
`0.34
`(-1.40, -0.26)
`-0.21
`-0.86
`0.65
`0.37
`(-1.47, -0.25)
`-0.48
`-0.01
`-0.47
`0.35
`( -1.05,0.11 )
`-0.37
`-0.38
`0.00
`0.40
`(-1.5,0.03 )
`-0.34
`-0.56
`0.22
`0.36
`(-0.43,0.89 )
`-0.27
`-0.50
`0.23
`0.40
`(-1.01,0.36 )
`-0.63
`-0.30
`-0.32
`0.41
`(-1.01,0.36 )
`-0.30
`0.37
`0.66
`0.41
`(-0.02, 1.4 )
`-0.31
`-0.45
`0.14
`0.44
`(-1.7,0.27 )
`
`Day
`
`1
`
`1
`1.5
`2
`3
`4
`8
`12
`23.5
`
`Day
`
`1
`
`Table 13: Summary of AQRS Analysis: RA001 50 mi; versus Placebo (D vs. B)
`Mean~QRS
`Time-
`Treatment Difference: ~~QRS
`TRT:C
`Hour
`TRT:B
`Estimate
`90%CI
`S.E.
`0.5
`0.33
`0.17
`0.15
`0.34
`(-0.41,0.72)
`-0.59
`0.05
`0.65
`0.37
`(-1.21,0.02)
`-0.04
`-0.01
`-0.03
`0.35
`(-0.61,0.55)
`-0.04
`-0.04
`0.00
`0.40
`(-0.71,0.63)
`0.22
`0.22
`0.00
`0.36
`(-0.58,0.59)
`-0.17
`-0.50
`0.32
`0.40
`(-0.33,0.99)
`-0.30
`0.30
`0.60
`0.41
`(-0.08, 1.28)
`-0.30
`0.50
`0.79
`0.41
`( 0.12, 1.47)
`-0.14
`-0.28
`0.14
`0.44
`(-1.00,0.45)
`
`1
`1.5
`2
`3
`4
`8
`12
`23.5
`
`5.3 CLINICAL PHARMACOLOGY ASSESSMENTS
`
`QTcF at predose was used as baseline. The relationship between MQTcF and RADOOI
`concentrations is visualized in Figure 5 with no evident exposure-response relationship
`over a dose range of20-50 mg QD.
`
`16
`
`

`

`0
`
`Figure 5. ~~ QTcF vs. RAOOI concentration.
`
`Everolimus 20 mg
`Everolimus 50 mg
`II
`
`II
`~i0
`
`cJ
`
`.
`
`II
`
`II
`
`0
`
`0
`0
`
`0
`
`0
`
`II
`
`0
`
`100
`150
`200
`Everolimus concentration (ng/mL)
`
`250
`
`0
`
`II
`
`0
`
`50
`
`II
`o
`
`II
`
`II
`
`II
`
`o
`
`Oil
`
`II
`
`II
`
`II
`
`0
`
`II
`
`II
`
`il
`
`o
`
`10
`
`lI
`
`o
`
`o
`
`II
`
`100
`
`Everolimus concentration (ng/mL)
`
`o
`
`o
`
`a
`
`17
`
`fig
`
`"0
`Q)
`¡¡
`.2, 40
`-0
`)c
`ã)
`g¡ 20
`.0
`-0c
`.a
`~ 0
`mi5
`Eo
`~-20
`Olc
`m..u
`LLu
`I-a
`
`m Q
`
`mo
`
`íi
`-S
`"0
`~
`:6 40
`m
`Q)
`.~
`Q)
`en
`m 20
`.0
`"0c
`.c
`Q)
`i
`E
`.g
`Q) -20
`0)
`c
`m
`.c
`.u
`I-a
`
`m0
`
`umi
`
`uu
`
`

`

`5.4 CLINICAL ASSESSMENTS
`
`5.4.1 Safety assessments
`
`None of
`
`the events identified to be of
`
`the ICH E 14 guidelines i.e.
`syncope, seizure, significant ventricular arrhythmias or sudden cardiac death occurred in
`this study.
`
`clinical importance per
`
`5.4.2 ECG assessments
`Waveforms from the ECG warehouse were reviewed. According to ECG 'warehouse
`statistics over 96% of the ECGs were annotated in the primary lead II, with none of the
`ECGs reported to have significant QT bias, according to the ECG warehouse automated
`algorithm. Overall, ECG acquisition and interpretation in this study appears acceptable.
`
`5.4.3 PR and QRS Interval
`There were no clinically significant effects due to RADOO 1 on the PR and QRS intervals
`the 90% CI ofthe difference compared to placebo being
`3.3 ms and 1.5 ms for the PR and QRS intervals respectively.
`
`with the largest upper bound of
`
`APpears Th\S Way
`On o(\g\nol
`
`18
`
`

`

`6 APPENDIX
`
`Principal adverse
`events
`
`controlled study C2240 (irrespective of
`
`6.1 HIGHLIGHTS OF CLINICAL PHARMACOLOGY
`Therapeutic dose
`10 mg daily
`Maximum
`The phase 1 program was not designed to determine the maximum tolerated dose.
`RAD001 was in general well tolerated at daily doses up to 10 mg and weekly
`tolerated dose
`doses up to 70 mg.
`The commonest dose limiting adverse event in Phase 1 monotherapy studies was
`Grade 3 mucositis. Other dose limiting adverse events in these studies were
`Grade 3 fatigue, hyperglycemia and neutropenia.
`The most common adverse events occurring in ? 1 0% of patients in the placebo
`relationship) were stomatitis, anemia,
`asthenia, fatigue, rash, diarrhea, cough, anorexia, nausea, dyspnea, edema
`peripheral, pyrexia, constipation, vomiting, mucosal inflammation,
`hypercholesterolemia, headache, epistaxis, dry skin, pruritus and
`hypertriglyceridemia (SCS-Table 2-6). The frequencies ofthe most common AEs
`seen with everolimus were consistent between study C2240 and the pooled
`dataset (SCS- Table 2-8).
`Single Dose
`50 mg single oral dose in healthy subjects using the
`oncology tablet (Study C2118)
`4 mg single oral dose in healthy subjects using the
`transplant tablet (Study W105)
`10 mg daily and 70 mg weekly oral dose in oncology
`patients using the oncology tablet (Study C2102 CP report)
`Mean:l SD (%CV) Cmax and AUC
`(Study W105): 4 mg single oral dose in healthy subjects
`(n=4)
`Cmax = 43.1 :l 5.3 nglmL (CV = 12.4%)
`AUCo_oo = 373:l 112 ng.h/mL (CV = 30%)
`
`Exposures
`Achieved at
`Maximum Tested
`Dose
`
`Maximum dose
`tested
`
`Multiple Dose
`
`Single Dose
`
`Multiple Dose
`
`(Study C21 18): single 50 mg oral dose in healthy subjects
`(n=61)
`Cmax = 159.71 :l 39.51 nglmL (CV = 24.7%)
`Mean:l SD (%CV) Cmax and AUCo_. (Study C2102 CP