Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD4877 in Japanese Patients with Solid Tumors.

2011·0.58 MB·English

by  Esaki, Taito

23
ORIGINAL ARTICLE
Phase I Study to Assess the Safety, Tolerability and
Pharmacokinetics of AZD4877 in Japanese Patients with
Solid Tumors
Taito Esaki,* Takashi Seto,† Hiroshi Ariyama,* Shuji Arita,* Chinatsu Fujimoto,* Koichiro Tsukasa,*
Takuro Kometani,† Kaname Nosaki,† Fumihiko Hirai,† and Katsuro Yagawa§
Departments of *Gastrointestinal and Medical Oncology, and †Thoracic Oncology, National Kyushu Cancer
Center,Fukuoka,Japan;§AstraZenecaKK,Osaka,Japan
DOI:10.1111/j.1753-5174.2011.00034.x
ABSTRACT
Introduction. AZD4877isapotentEg5inhibitorthathasbeenshowntohaveanacceptabletolerabilityprofilein
aPhaseIstudyofWesternpatientswithsolidtumors.Thisstudywasconductedtoevaluatethesafety,pharmaco-
kinetic(PK)profile,maximumtolerateddose(MTD)andefficacyofAZD4877inaJapanesepopulationwithsolid
tumors.
Methods. InthisPhaseI,open-label,dose-escalationstudy,AZD4877(10,15,20or25mg)wasadministeredasa
1-hourintravenousinfusionondays1,8and15ofrepeated28-daycyclestoJapanesepatientswithadvancedsolid
tumors. Adverse events (AEs) were evaluated according to Common Terminology Criteria for Adverse Events
(CTCAE)version3.0.PKvariableswereassessedpre-andpostdosing.TheMTDofAZD4877wasdeterminedby
evaluatingdose-limitingtoxicities(DLTs).EfficacywasevaluatedbyassessingbestresponseaccordingtoResponse
EvaluationCriteriaInSolidTumorsversion1.0.
Results. Of the 21 patients enrolled, 18 received at least one dose of AZD4877 (N=3 in both the 10 and 15mg
cohorts,N=6inboththe20and25mgcohorts).ThemostcommonlyreportedAEswerefatigueandnausea(39%
of patients each). One patient in each of the 20 and 25mg cohorts experienced a DLT (neutropenia and febrile
neutropenia).Doseescalationwashaltedat25mgandtheMTDwasnotdefinedinthispopulation.CTCAEgrade
(cid:2)3 abnormal laboratory findings/vital signs were reported in 12 patients, with neutropenia (56%) and leukopenia
(44%) being the most commonly reported. Exposure to AZD4877 was not fully dose proportional and AZD4877
clearanceandeliminationhalf-lifeappearedindependentofdose.ThebestresponsetoAZD4877wasstabledisease
infiveof16evaluablepatients.
Conclusion. AZD4877 up to doses of 25mg was well tolerated in Japanese patients. There was little evidence of
clinicalefficacy.
KeyWords. AZD4877;Eg5Inhibitor;SolidTumors;Japanese
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Introduction
Studytype:Openlabel,doseescalation
Kinesin spindle protein, also known as Eg5,
Studyphase:PhaseI
is a microtubule motor protein essential for
Study registration number: ClinicalTrials.gov,
NCT00613652 the formation of a bipolar mitotic spindle and
©2011,ArchivesofDrugInformation ArchDrugInfo2011;4:23–31
24 Esaki etal.
normal centrosome separation during mitosis [1]. nisminaclinicalsetting.Thebestobjectivetumor
Eg5 expression is elevated in several proliferative responsetoAZD4877wasonlystabledisease[17].
tissues,includingthethymus,tonsil,testis,esoph- The aim of this Phase I study was to evaluate
ageal epithelium and bone marrow, as well as in the safety, pharmacokinetic (PK) profile, maxi-
a number of solid tumors and leukemias [2–4]. mum tolerated dose (MTD) and efficacy of
Inhibition of Eg5 in replicating cells has been AZD4877 in Japanese patients with solid tumors.
shown to prevent centrosomal separation and
mitotic spindle assembly, which leads to the for-
mation of monopolar spindles (“monoasters”), Methods
activation of the spindle checkpoint and mitotic
Patients
arrest, resulting in cell death [1,5,6].
Patients with advanced solid malignancies aged
First generation antimitotic drugs, such as the
20–75 years were included if they had a histologi-
taxanesandvincaalkaloids,havebeenshowntobe
cally or cytologically confirmed solid malignancy
effectiveanticanceragents[7].However,bytarget-
for which no standard curative or palliative mea-
ing tubulin, these agents affect the microtubular
sures existed or were no longer effective, and a
architectureofnon-proliferatingcells,whichleads
WorldHealthOrganization(WHO)performance
to a high incidence of neurotoxic side effects
status of 0 or 1. Patients who had received prior
as well as myelosuppression [8,9]. Eg5 is not
treatmentwithananticanceragentwithin28days
expressedinnon-proliferatingcellsorintheadult
of the first dose of study treatment (6 weeks for
peripheral nervous system, and so inhibition of
mitomycin treatment) were excluded from the
Eg5onlytargetsactivelymitoticcells[10].There-
study. Other exclusion criteria included absolute
fore, Eg5 inhibitors are not expected to cause the
neutrophil count <1.5¥109/L, platelet count
neurotoxic side effects commonly observed with
<100¥109/L, hemoglobin (cid:3)9g/dL, inadequate
traditional antimitotic agents [2,11]. Inhibition
renal function (creatinine >1.3¥ upper limit of
of Eg5 has been shown to cause cell death in a
normal [ULN]) or liver function (serum bilirubin
number of preclinical cancer cell lines and to
>1.5¥ ULN) as well as evidence of severe or
have antiproliferative activity in human tumor
uncontrolled systemic disease.
xenograft models [11–15].
Allpatientsprovidedwritteninformedconsent.
AZD4877isapotentinhibitorofEg5thatpre-
Thestudywasapprovedbytheindependentethics
vents centrosome separation and mitotic spindle
committeeforthetrialcenterandwasconductedin
assembly resulting in mitotic arrest, induction of
accordancewiththeDeclarationofHelsinki[18].
apoptosis and cell death. AZD4877 was shown to
inhibitgrowthofabroadpanelofsolidandhema-
tologictumorcelllines[16].Furthermore,activity Study Design
was observed in human tumor xenograft models This was a Phase I, open-label, single-center,
including a primary bladder tumor model and the dose-escalation study in Japanese patients
rituximab-insensitive non-Hodgkin’s lymphoma (ClinicalTrials.gov identifier NCT00613652).
model,DoHH2T53.InaPhaseIstudyinWestern AZD4877 was administered at escalating doses in
patients, AZD4877 25mg was shown to have an separatecohortsofpatientsstartingat10mggiven
acceptable tolerability profile with evidence of as a 1-hour intravenous (iv) infusion on days 1, 8
monoaster formation suggesting proof of mecha- and 15 of a 28-day cycle (Figure1). The next
Figure1 Studydesign.
ArchDrugInfo2011;4:23–31
Phase I Study of AZD4877 in Solid Tumors 25
patientcohortreceivedthenexthighestdoselevel concentration–time curve (t ), mean residence
12λz
based on assessment of dose-limiting toxicities time (MRT), apparent volume of distribution
(DLTs). The MTD was identified as the highest at steady state (V ) and total apparent plasma
ss
dose at which no more than one of six patients clearance (CL). Non-compartmental methods
experienced a DLT during cycle 1. Following were used for the evaluation of the plasma
completion of cycle 1, patients could receive con- concentration–timedataandC wasdetermined
max
secutive treatment with AZD4877 if they contin- by inspection of the concentration–time profiles.
uedtobenefitandtherewasnoevidenceofdisease Where possible, the terminal elimination rate
progression. constant(l)wascalculatedbylog–linearregression
of the terminal portion of the concentration–
Objectives time profiles, and t was defined as 0.6932/l .
12λz Z
Theprimaryobjectivesofthisstudyweretoinves- AUC wasdeterminedusingthelineartrapezoi-
0–24h
tigate the safety, tolerability and PK profile of dal rule, and where appropriate, AUC was
0–24h
AZD4877. The secondary objective was to evalu- extrapolated to infinity using l to obtain AUC
0–•
atetheMTDofAZD4877basedonassessmentof values.MRTwascalculatedastheratioofthearea
DLTs. Exploratory objectives included assessment under the first moment curve (AUMC) to AUC
of the antitumor activity of AZD4877 and evalua- plustheinfusionduration/2.Totalapparentclear-
tion of serum levels of the tumor cell death bio- ance was calculated from the ratio of dose/AUC
markersM30(caspase-cleavedcytokeratin18)and and V was determined from the MRT¥CL.
ss
M65 (cytokeratin 18). The methods for the PK parameter assessments
and calculations reported in this study have been
Assessments describedpreviously[19].
Safety and tolerability were evaluated by assess- The tumor cell death biomarkers M30 and
ment of adverse events (AEs) according to M65 have previously been shown to be elevated
Common Terminology Criteria for Adverse in patients with a variety of cancers and are
Events (CTCAE) version 3.0. Laboratory assess- considered to be measures of apoptosis and
ments (clinical chemistry and hematology) were tumor burden. Blood samples for M30 and M65
undertaken using samples collected pre-dose and biomarker assessment were taken pre-dose and at
on days 1, 8, 15 and 22 of cycles 1 and 2, and 24, 48, 72, 96 and 120 hours after infusion and
urinalysis was undertaken using samples collected on day 8 of cycle 1. Serum was extracted from
pre-doseandondays1,8and15ofcycle1andon whole blood samples (3mL) by centrifugation
day 1 of subsequent cycles. (1,000¥g at 4°C) and stored at -20°C until
The MTD of AZD4877 was defined as the required. Biomarker analysis was performed in
highest dose at which no more than one of six duplicate by the Experimental Pharmacology
evaluablepatientsexperiencedaDLTduringcycle Group, Paterson Institute of Cancer Research,
1. DLTs were defined as grade 3 or 4 hemolysis, University of Manchester (UK). Baseline cor-
grade 4 hematologic toxicity (thrombocytopenia rected values were calculated by subtracting the
orneutropenia >4days),grade3or4neutropenia mean of the two pre-dose values from the post-
complicated by fever (oral temperature (cid:2)38.5°C; dose values.
axillary temperature (cid:2)38.0°C), grade 2 diarrhea Efficacy was determined by investigator assess-
>4daysdespiteoptimalmanagement,grade3or4 ment of overall best response according to
vomiting for >24 hours despite suitable anti- Response Evaluation Criteria In Solid Tumors
emetics or other grade 3 or 4 non-hematologic (RECIST) version 1.0. Baseline radiologic tumor
toxicity. assessments were performed within 28 days prior
Blood samples for PK analysis were collected toadministrationofthefirstdose,andsubsequent
daily at various timepoints pre- and post-dose on tumor evaluations were performed on day 29 of
days 1–8 of cycle 1, and day 1 of cycle 2. PK cycles 1 and 2 and subsequent odd numbered
parameters evaluated included maximum plasma cycles. The minimum period of stable disease was
drugconcentration(C ),plasmadrugconcentra- defined as 8 weeks.
max
tion24hoursafteradministration(C ),areaunder
24h
theconcentration–timecurvefromzerotoinfinity StatisticalAnalysis
(AUC ),areaundertheconcentration–timecurve Dataaresummarizeddescriptivelybydosegroup.
0–•
from zero to 24 hours (AUC ), half-life associ- Duetothelimitednumberofpatientsexpectedin
0–24h
atedwiththeterminalslopeofasemi-logarithmic each dose group (N=3–6 per group), no formal
ArchDrugInfo2011;4:23–31
26 Esaki etal.
Table1 Patientdemographicsandbaselinecharacteristics
AZD4877dose†
10mg(N=3) 15mg(N=3) 20mg(N=6) 25mg(N=6) Total(N=18)
Age(years)
Mean(SD) 66.7(4.0) 62.7(5.5) 62.2(10.7) 61.3(9.6) 62.7(8.4)
Range 63–71 59–69 45–73 50–75 45–75
Gender,N(%)
Male 2(67) 2(67) 1(17) 2(33) 7(39)
Female 1(33) 1(33) 5(83) 4(67) 11(61)
WHOperformancestatus,N(%)
Normalactivity(0) 1(33) 3(100) 2(33) 2(33) 8(44)
Restrictedactivity(1) 2(67) 0 4(67) 4(67) 10(56)
Primarytumorsite,N(%)
Lung 1(33) 0 3(50) 2(33) 6(33)
Breast 0 1(33) 0 2(33) 3(17)
Pleura/pleuraleffusion 0 0 1(17) 0 1(6)
Prostate 0 1(33) 0 0 1(6)
Stomach 0 0 1(17) 0 1(6)
Colon 1(33) 0 0 0 1(6)
Other‡ 1(33) 1(33) 1(17) 2(33) 5(28)
†Doseassignedonday1ofcycle1.
‡Othertumorsitesinclude:thymus(2),ureter(1),renal/prostate(1)andprimaryunknowntumor(1).
SD=standarddeviation;WHO=WorldHealthOrganization.
statistical comparisons between dose groups were nausea (39%), and pyrexia (33%) (Table2). The
planned or conducted. majority of these were mild or moderate in inten-
sity (CTCAE grade 1 or 2). Three patients expe-
rienced CTCAE grade (cid:2)3 events; one in the
Results
20mg dose cohort experienced grade 4 neutrope-
Patient Characteristics niaandtwointhe25mgdosecohortexperienced
A total of 21 patients were enrolled in this study grade 4 febrile neutropenia and grade 3 constipa-
during January 2008 to June 2009. Of the 21 tion, fatigue, urinary tract infection and anorexia,
patients,18receivedatleastonedoseofAZD4877 respectively (Table3a). There were no deaths
ranging from doses of 10 to 25mg (Table1). The during the study.
mean age of patients was 62.7 years and 11 Twopatientsinthe20and25mgcohortsexpe-
(61.1%) were female. All patients had advanced rienced DLTs; CTCAE grade 4 neutropenia and
solid malignancies with a broad representation of febrile neutropenia, respectively. Grade 3 consti-
primary tumor types, of which lung (33.3%) and pation, fatigue, urinary tract infection and anor-
breast cancer (16.7%) were the most common. exia were not considered to be DLTs because
Seventeen of 18 patients discontinued study they occurred 1 week after the completion of
treatment due to lack of therapeutic response and cycle1andwerenotconsideredcausallyrelatedto
one patient in the 20mg dose cohort withdrew
from the study due to an AE (grade 2 cystitis).
The median duration of treatment across all Table2 CTCAEofanygradereportedin(cid:2)20%of
patientsoverall
doses of AZD4877 was 50 days (range 15–163),
with the longest median duration of 100 days PatientswithAEs,N(%)
(range 45–133) being in the 10mg dose cohort. AZD4877dose
The median number of treatment cycles initiated 10mg 15mg 20mg 25mg Total
across all doses was 2 (range 1–6). Of the 18 (N=3) (N=3) (N=6) (N=6) (N=18)
patients treated with AZD4877, only seven were Fatigue 1(33) 1(33) 2(33) 3(50) 7(39)
continuing to receive their fully assigned dose by Nausea 2(67) 1(33) 1(17) 3(50) 7(39)
Pyrexia 0 3(100) 2(33) 1(17) 6(33)
day 1 of cycle 2.
Diarrhea 2(67) 1(33) 0 2(33) 5(28)
Dizziness 2(67) 0 3(50) 0 5(28)
Rash 0 3(100) 2(33) 0 5(28)
Safety
Constipation 1(33) 0 1(17) 2(33) 4(22)
All patients experienced at least one AE, of which Nasopharyngitis 0 0 2(33) 2(33) 4(22)
Insomnia 1(33) 0 2(33) 1(17) 4(22)
the most commonly reported were fatigue (39%),
ArchDrugInfo2011;4:23–31
Phase I Study of AZD4877 in Solid Tumors 27
treatment by the investigator. The 20 and 25mg leukopenia (44%). The incidence of neutropenia
dose cohorts were therefore expanded to six increased in an approximately dose-proportional
patients,however,nofurtherDLTswereobserved. manner,withfiveofsixpatientsinthe25mgdose
TwelvepatientsexperiencedCTCAEgrade(cid:2)3 cohort experiencing grade (cid:2)3 neutropenia
abnormal laboratory findings/vital signs, the most (Table3b). Overall, the nadir in the laboratory
common of which were neutropenia (56%) and hematology variables of white blood cell count,
platelet count and absolute neutrophil count
occurred by day 15 of cycle 1 (Table3c). There
Table3a CTCAEgrade(cid:2)3eventsreportedbyanypatient werenootherclinicallyrelevantchangesortrends
inlaboratoryparametersorvitalsigns(WHOper-
Patientswithgrade(cid:2)3event,N(%)
formance status, physical findings or ECG obser-
AZD4877dose
vations) over the dosing range.
10mg 15mg 20mg 25mg Total
(N=3) (N=3) (N=6) (N=6) (N=18)
Pharmacokinetics
Anygrade(cid:2)3event 0 0 1(17) 2(33) 3(17)
Febrileneutropenia 0 0 0 1(17) 1(6) Systemic exposure to AZD4877 (as calculated by
Neutropenia 0 0 1(17) 0 1(6) C , AUC , C and AUC ) increased in an
max 0–• 24h 0–24h
Constipation 0 0 0 1(17) 1(6)
approximatelydose-proportionalmannerinthe10
Fatigue 0 0 0 1(17) 1(6)
Urinarytract 0 0 0 1(17) 1(6) and 15mg cohorts, however, greater than dose-
infection proportionalincreaseswereobservedbetweenthe
Anorexia 0 0 0 1(17) 1(6)
10 and 20mg cohorts and little change was
Table3b CTCAEgrade(cid:2)3abnormallaboratoryfindings/vitalsignsreportedbyanypatient
Patientswithgrade(cid:2)3abnormallaboratoryfindings/vitalsigns,N(%)
AZD4877dose
10mg(N=3) 15mg(N=3) 20mg(N=6) 25mg(N=6) Total(N=18)
Anygrade(cid:2)3finding/vitalsign 1(33) 1(33) 4(67) 6(100) 12(67)
Neutropenia 1(33) 1(33) 3(50) 5(83) 10(56)
Leukopenia 0 0 3(50) 5(83) 8(44)
Lymphopenia 0 0 0 1(17) 1(6)
Thrombocytopenia 0 0 0 1(17) 1(6)
Bloodsodiumdecreased 0 0 1(17) 0 1(6)
Hemoglobindecreased 0 0 0 1(17) 1(6)
Lymphocytecountdecreased 0 0 0 1(17) 1(6)
Weightdecreased 0 0 1(17) 0 1(6)
Cut-off value for values for defining grade (cid:2)3 abnormal laboratory finding: neutropenia <1.0¥109/L; leukopenia <2.0¥109/L; lymphopenia: <0.5¥109/L;
thrombocytopenia:<50.0¥109/L;bloodsodiumdecreased:<130mmol/L;hemoglobindecreased:<8.0g/dL;lymphocytecountdecreased:<0.5¥109/L;weight
decreased:(cid:2)20%frombaseline.
Table3c Selectedlaboratoryhematologyvariablesatbaselineandduringcycle1
AZD4877dose
Parameter,mean(SD) 10mg(N=3) 15mg(N=3) 20mg(N=6) 25mg(N=6) Total(N=18)
Whitebloodcellcount,103/mL
Baseline 4.28(0.91) 6.95(1.46) 6.03(3.08) 4.94(1.28) 5.53(2.11)
Cycle1,Day8 4.13(0.63) 5.50(1.48) 2.97(1.06) 3.01(0.99) 3.60(1.37)
Cycle1,Day15 3.59(0.69) 4.66(2.19) 2.82(1.20) 1.58(0.57) 2.84(1.55)
Cycle1,Day22 4.09(0.66) 4.53(1.70) 2.64(0.69) 2.73(0.68) 3.23(1.14)
Plateletcount,103/mL
Baseline 233.3(69.3) 242.3(21.5) 279.2(40.2) 276.5(71.7) 264.5(54.7)
Cycle1,Day8 227.3(36.7) 229.0(35.9) 245.7(45.5) 246.5(99.7) 240.1(62.6)
Cycle1,Day15 203.3(46.5) 217.0(6.1) 265.2(79.5) 184.5(85.1) 219.9(73.9)
Cycle1,Day22 205.0(54.0) 232.0(7.9) 262.2(48.0) 308.7(117.3) 263.1(81.1)
TotalANC,103/mL
Baseline 2.48(0.38) 4.36(0.87) 4.34(2.95) 3.39(1.38) 3.72(1.94)
Cycle1,Day8 2.00(0.37) 3.23(1.26) 1.81(0.99) 2.00(0.97) 2.14(1.01)
Cycle1,Day15 1.25(0.27) 2.33(1.62) 1.49(0.82) 0.57(0.50) 1.28(0.99)
Cycle1,Day22 1.68(0.35) 2.30(1.50) 1.25(0.69) 1.41(0.48) 1.55(0.79)
ANC=absoluteneutrophilcount.
ArchDrugInfo2011;4:23–31
28 Esaki etal.
Figure2 Geometric mean plasma
concentrationofAZD4877versustime
by dose level following single dosing.
SD=standarddeviation.
observed between the 20 and 25mg cohorts cycle1.Consistentwiththisfinding,peaksinthese
(Figure2). MRT, t and V values remained biomarkers were observed in the 20 and 25mg
12λz SS
relatively unchanged in the 15, 20 and 25mg dose cohorts on days 1 and 2, potentially indicat-
cohorts, however, higher values for each of these ingwavesofdrug-inducedcelldeathattheearlier
parameters were reported in the 10mg cohort timepoints.Adifferentprofilewasobservedforthe
(Table4). Clearance of AZD4877 was similar in 10mg dose with no reduction in levels of M30 or
the 10, 15 and 25mg cohorts (19.5 to 22.4L/h) M65 by day 8. Mean percentage changes from
but lower in the 20mg cohort (14.0L/h). baselineforM30andM65valueswithinthefirst8
days of therapy are shown in Figure3. In the
Biomarkers AZD487720and25mgcohorts,decreasesinboth
Overall, there was an approximately 15% mean biomarkers were observed from days 3 to 8. Fur-
decrease from baseline in the tumor cell death thermore, changes from baseline of >30% were
biomarkers,M30andM65inthe15,20and25mg observedforseveralpatientsoverthe8-dayassess-
dose cohorts over the 8-day assessment period of ment period (Figure4).
Table4 PharmacokineticparametersofAZD4877duringcycle1
AZD4877dose
PKparameter 10mg(N=3) 15mg(N=3) 20mg(N=6) 25mg(N=6)
C (ng/mL) 63.4(22.4) 99.7(59.0) 218.0(51.2) 224.0(15.8)
max
C (ng/mL) 4.9(13.4) 7.8(55.3) 14.9(38.9) 13.6(47.8)
24h
AUC (ng·h/mL) 447.0(20.0) 671.0(60.5) 1430.0(33.5) 1280.0(19.4)
0–•
AUC (ng·h/mL) 234.0(17.6) 424.0(45.3) 882.0(32.3) 838.0(15.9)
0–24h
t12λz(h) 28.7(9.0) 20.3(32.5) 21.3(45.9) 21.1(27.7)
MRT(h) 34.2(8.9) 22.9(36.3) 22.4(59.7) 22.2(26.1)
V (L) 766.0(11.6) 512.0(37.3) 314.0(52.3) 432.0(24.6)
SS
CL(L/h) 22.4(20.0) 22.3(60.5) 14.0(33.5) 19.5(19.4)
Dataareexpressedasgeometricmean(CV%).
AUC0–•=areaundertheplasmaconcentration–timecurvefromzerotoinfinity;AUC0–24h=areaundertheplasmaconcentration–timecurvefromzeroto24hours;
C24h=plasmadrugconcentration24hoursafteradministration;CL=totalbodyclearanceofdrugfromplasma;Cmax=maximumplasmadrugconcentration;
CV=coefficientofvariation;MRT=meanresidencetime;SD=standarddeviation;t =half-lifeassociatedwiththeterminalslope(lz)ofasemi-logarithmic
concentration–timecurve;VSS=volumeofdistributionatsteadystate. 12λz
ArchDrugInfo2011;4:23–31
Phase I Study of AZD4877 in Solid Tumors 29
Figure3 Meanchangefrombaseline(%)in(A)M30and(B)M65valueswithinthefirst8daysofcycle1.
Efficacy patients with a range of solid tumors. The most
No patients experienced a complete or partial commonly reported CTCAE grade (cid:2)3 abnormal
response. The overall best response was stable laboratory findings/vital signs was neutropenia,
disease(cid:2)8weeks,whichwasobservedinfiveof16 which was dose related. Two patients in the 20
evaluable patients; two in the 10mg cohort (one and 25mg cohorts experienced DLTs, of grade 4
lung and one ureter cancer), one in the 15mg neutropenia and febrile neutropenia, however,
cohort (renal/prostate cancer) and two in the there were no more DLTs when the cohorts were
20mg cohort (one lung and one thymus). The expanded. In a parallel US study, patients with
patient in the 20mg cohort with thymus cancer solid tumors receiving AZD4877 30mg experi-
had stable disease for (cid:2)12 weeks. enced neutropenia, which led to 25mg being
defined as the recommended dose for further
evaluation [17]. Consequently, the MTD for
Discussion
AZD4877 was not defined in Japanese patients.
AZD4877 monotherapy at doses up to 25mg Systemic exposure to AZD4877 was not fully
weekly was generally well tolerated in Japanese dose proportional, which may be due to the small
Figure4 Change(%)in(A)M30and(B)M65frombaselineonday1today8forindividualpatients.
ArchDrugInfo2011;4:23–31
30 Esaki etal.
number of patients in each cohort. Despite this, 2 Sakowicz R, Finer JT, Beraud C, Crompton A,
the PK parameters for AZD4877 in Japanese Lewis E, Fritsch A, etal. Antitumor activity of a
patients were comparable with those reported in kinesininhibitor.CancerRes2004;64:3276–80.
3 Hedge PS, Cogswell J, Carrick J, Jackson J, Wood
Western patients [17]. Although reductions in the
KW, Eng WK, etal. Differential gene expression
levelsofthetumorcelldeathbiomarkersM30and
analysis of kinesin spindle protein in human solid
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tumors. Proc Am Soc Clin Oncol 2003;22:abst
burden, were noted within the first 8 days of
535.
therapy the best response to AZD4877 was stable
4 CastilloA,MorseHC,III,GodfreyVL,NaeemR,
disease (cid:2)8 weeks. Similarly, the best response to Justice MJ. Overexpression of Eg5 causes genomic
weekly treatment with AZD4877 in Western instabilityandtumorformationinmice.CancerRes
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This limited clinical response is similar to that 5 Compton DA. Spindle assembly in animal cells.
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In conclusion, treatment with AZD4877 is fea-
inductionofapoptosisbyanti-microtubuleagentsin
sible in Japanese patients with advanced solid
human lung cancers. Am J Pathol 2003;163:1109–
tumors. The best objective tumor response to
16.
AZD4877 was only stable disease. Because of the
7 Jordan MA. Mechanisms of action of anti-tumor
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completed Phase I and II trials of AZD4877, CurrMedChemAnticancerAgents2002;2:1–17.
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future of the mitotic spindle as an oncology target.
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fromtheExperimentalPharmacologyGroup,Paterson
10 Mayer TU, Kapoor TM, Haggarty SJ, King RW,
InstituteofCancerResearch,UniversityofManchester,
SchreiberSL,MitchisonTJ.Smallmoleculeinhibi-
Manchester, UK; Michael Malone from the Clinical
tor of mitotic spindle bipolarity identified in a
Biomarker Group, AstraZeneca, Alderley Park,
phenotype-basedscreen.Science1999;286:971–4.
Macclesfield, UK and Fred Zheng from the Clinical
11 ZhangY,XuW.Progressonkinesinspindleprotein
Biomarker Group, AstraZeneca, Wilmington, DE,
inhibitors as anti-cancer agents. Anticancer Agents
USAfortheiranalysisofthecelldeathmarkerdata.We
MedChem2008;8:698–704.
would also like to thank Claire Routley PhD, from
12 HayashiN,KollerE,FazliL,GleaveME.Effectsof
Mudskipper Bioscience, who provided medical writing
Eg5 knockdown on human prostate cancer
assistancefundedbyAstraZeneca.
xenograft growth and chemosensitivity. Prostate
Corresponding Author: Taito Esaki, MD, Depart- 2008;68:1283–95.
ment of Gastrointestinal and Medical Oncology, 13 KapoorTM,MayerTU,CoughlinML,Mitchison
National Kyushu Cancer Center, 3-1-1, Notame, TJ. Probing spindle assembly mechanisms with
Minami-ku, Fukuoka 811-1395, Japan. Tel: (81) monastrol,asmallmoleculeinhibitorofthemitotic
92-541-3231; Fax: [phone]; E-mail: tesaki@ kinesin,Eg5.JCellBiol2000;150:975–88.
nk-cc.go.jp 14 LiuM,YuH,HuoL,LiuJ,LiM,ZhouJ.Validat-
ingthemitotickinesinEg5asatherapeutictargetin
Conflict of Interest: This study was supported by pancreaticcancercellsandtumorxenograftsusinga
AstraZeneca. Katsuro Yagawa was an employee of specific inhibitor. Biochem Pharmacol 2008;76:
AstraZenecaatthetimeofthisstudy.Allotherauthors 169–78.
havenodisclosures. 15 NakaiR,IidaS,TakahashiT,TsujitaT,OkamotoS,
Takada C, etal. K858, a novel inhibitor of mitotic
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