“iltI£tisil'il:dCEF" at-rnactually Ilaceived
`an tlo-zr increase in dos: lnlzrtsily cont-
`pared in those in the standard CEF
`arvttllttqttality orlile was also stxscssed.
`la the lil nlllllntlltzul pflIlEnLt. no
`diflcrutou httween the two arms were
`reserved witlt rfipuil ID tesptrnse rates
`nt progression-tree survival. Htlwcver.
`me intensified regimen was associated
`wiih nlotleloucily. Grade 3 and t events
`were more lrcquent with intensified
`car than with the standard regimen
`(anemia. lash vs 35: l¢uki‘tpt:tiia_ 2m.
`vs 5%; thmrtthtxylnpenin, sat vs 2%;
`and rt-tttcnsitis. me vs 3%).
`High-Dust chetnotherapy .
`with SLeni-Cell srrpptn-t
`Regarding dose es.-alatiptt, the po-
`lutlial title of ltigli-dnse chemnllienpy
`with stern-cell rum: still awaits tkfi-
`uitiun. Although some atlthurs llavl: re-
`ported 5-year disease-{tee survival
`proportions at appmxitnately 20% ill
`stdecled patients lntaied with such regi-
`l|'I£lIS,[9,lU] in dalz Iliare has been no
`demonstration of clear sitpenonly ol
`htghdose eottsalidalian nVI:i’IIl.hl'1x|rdl-
`egier in the trtatraget-rtutt of stage lv
`breast cancer.
`Most studies at high-dose Chemo-
`therapy have been uncontrolled phase I
`and II tritlr. trltt-rt matnpnrtipd hy the
`it-ruisiible. bill ptolrlemitlic and unfor-
`innate,rxrrnp.-tritottswith ltistnr-italcoir
`lruls. Maretzvet. the inherent bias of
`patient seleuiull forthese trials has also
`been an issue. The first repnned lan-
`chttiizcd trial of standard Ch¢lIIIXlIelI-
`py vx liiglbdnlz chernatherapy with
`either zrrtottrgttus hope marrow or pe-
`rlplteral ltltmd slctn-ttll sitpptri. wri-
`dltcltd by Bczwutl: er nl, showed that
`higli-dust: thmpysigtrititarttly :tttr.ttl‘l-
`ed the dunllittlisr of response and
`S|l|'VlVil." I] However, the ml:t1iatiloI-
`low-up was only 72 wants. the study
`was small. and the standard-dose clic-
`matherapy amt has bent criticiwd lur
`heittg stthoptittttl.
`Al III: I993 ASCO meeting. several
`nruseutatwtts evaluated tlilferertl trarts—
`plant mndaltties. is, single vs tandem
`ltiglldosecl:
`y, latldtetti vs iri-
`ple lilgltslose chenltitlicnpy. and purg-
`ing prttrrtror mils lmtn peripheral bland
`slettl eells.[lz.l1l the ctplatalory na-
`ture at these trials and preliminary re-
`sltlls underscore the need for large.
`praspective clittical
`tmls ta address
`these question.
`
`docetaxel therapy praved mate effec-
`ti
`than
`Ia
`'
`pl
`' bl
`'
`,
` mg
`ngitnnly
`myclrt mili Vin nunti;
`Cottthinations oftwn.thr=. trr rrtore
`and
`ta treauuznt failure. but. trtnst
`cllemothcttrpeulic agcntsutroccllsnll-
`gnulylllglt, with trgaltl to tmvlval
`Meclita survivnt duration was t [.4
`tilyerltplnyed based on pteelinitaluata
`strggtstitrg iniprttvatl atilinitrltracilvity
`rt-utntlts in the doeuaxel group vs 8.1
`(ie. ttlttitive or synergistic eltects);
`multtlts in the nlitntttycin-vitthlastirte
`maltynrthtse mrrthirtatirrrtsare derivcd
`st-mp (P: -0097)-l5l
`empirically. liov/evu. Alillrtuyi enm-
`In this troptettt, the experience of
`hinaiittn regimens tnaysornatilnes yield
`Sledge and colleagues. tepnrw II the
`higher rupntlse pmptmims than sitt-
`1997 ASCO trading. sltultld be con-
`gle-llgetlt therapy. this can nlazunt Ill:
`sitht:d.l‘l] In that study, Eastern Coop-
`east of greater toxicity. perhaps result-
`erative otraotogycmup sutdy(t-DOG)
`ing in Ill ova-Ill lniilcl tltel-apeutic ill-
`H93. sitigl:-agzttt therapy with either
`dtx.[4] This issue was specifically
`dnmruhicilt or ptlclitaltel (Taml) was
`cotnpxtw wiiltih: t:ttlnhinau'onol'dua-
`addressed Ily lwn studies presented ll
`lhezlathutrrttal nteetingprthe anten-
`Drlllllcili tntl paclilaxel u lirst-litre
`can society of Clinical Oncology
`tltenpy in 739 patient with muasiatit:
`(ASCO) l.l'l I998.
`htustcarteer. Patients receiving single-
`agent therapy were crusted met In the
`The fitst study. conducted by the
`Finnish Breast Cancer Group, modalit-
`othavngerttatlutimeoldiseaseprn-
`yrs.-tiprt
`ized303 hrmtrancrrpatienttwllltdw
`
`Monothenpy with either doaonllti-
`taut ttraasusrs nu cine oflwo tegitnetu
`( l) single-aguitrillzmodietipy with epi-
`tin or paelitartel hart equivalent thera-
`nililitlll (20 ntg/tnwtrratly tlnlil rlrsras-.
`peuli: activity: the eottiairlalinrt at the
`progxessintl or a cumulative duse uf
`two drugs ruulted in superior overall
`tespunsem:andtiuletottehtmentlail-
`l,(XD myttfl, followed by nlilclnycin
`(ll rttg/nttevtry 4 tveelts) as seetrrtd-lirte
`tne Dapite this. cctnllitialimi tllaapy
`was not sttperiur to sutueatdlal single-
`therapy: or('1) the CEFpvlychelrlol.ilu-
`any regimen. consisting ol t:yl:lapltus-
`llgetlttilerapy with regardtnavenll stir-
`pliamide (500 trig/tn’), epirtthicin (60
`vival and quality af life.
`Taken together. these trials should
`myth»), ind fliloruumcil (son ltiglm')
`evuy 3 weeks. follnwed by triitmnycin
`pmmtt a reccntsideratinn oi the mn-
`ventioml wisdom that cdulbinatinn
`(ll llifltn’) and vinblastine (6 mg/m’)
`every 4 weeks. Altltnttglt tnponset to
`cltnrlitlllienpy is the “guld,sra'rrrlatd"
`for Ihc trulntent of tvrtaslatit: breast
`Ci-;Ftmdadtnla:t mudcsllylougerthan
`cancer,
`responses in epirubitiu uluue (median
`
`diimlinii, 12 vs I05 Iltnnllte
`= .07)r
`Irt_M2Le.Er.t&r1
`nosigtlifilratll difierenee lnlim¢|Dpl'|>
`gxixaiuit ([7 :28) or evenll survival (P
`--.65)wasfuurtd bt.-twaeuthetwo arms.
`Ultilrtately.tlietrt-attitctllclstagclv
`Murwm, tlo difluelxe in survival
`hrrastratlraaflenreptlcsultsananempt
`was seen when only the patients uvhn
`intutzltattaqitililrrittrii bt=tvrra'.rlih:pal-
`received both the first- and second-line
`liatimr enrlkt-md by response in thera-
`py. on the one hand. and treat-
`uuttnstin were compared (F = .96). or
`ivlzn survival was calculatd from
`mant-related tnaicily.
`tilt the nther.
`This. the i§lte oi the value nl dose
`the beginning of secatld-line therapy
`intertsirtealintt is at ttlrnnsl inlputtanlae,
`(P: 56). Single-agzttt lllenpy was also
`sinneixnaseddoscsuewmmnnlyay
`ttssnciateil with less tmticity and better
`quality ofl.ifz.|S]
`meiatedwililgrutertoxieity.
`Th: second repcln. ptesettttsd by the
`Doselntensified Regimen
`ltil.u'na.liottalTa.It11ae3l11SllidyGlntlp,
`rtetcriherl the results of I plus: in
`A llill at the Italian gmllp Gruppo
`study mtttparitrg single-agpitl decentr-
`Onoolngiocl N0‘l'|’l‘()ilBl (GONG). re-
`el (laxmere) therapy vs the combina-
`ported at ASCO 1998 by Lionettn et al.
`tion of mittxnycin and vinblasiitte in
`is inntitctive in this regard. This trial
`parents with metastatic breast canm
`randtrrrtized patients in receive either
`standard doses ul CFJ7 lit the same reg-
`whns: disease had progressed lttllhtv-
`imen in all
`ilttetisilied manner with
`lug an nttthr-teyelinertnntaining regi~
`melt.
`lit its experience. siagleagenl
`growth fartnr snpptrn; patients in ate
`648
`DNODLOGV - VOLUME I3 ~ NUMBERS
`
`
`
`Astrazeneca Ex. 2010 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPR2016-01326
`
`
`MOMCA FORMER. MD
`PAMELA MUK§'l"EiI. MD
`ANDREW D. SEDMAN. MD
`Breast Cancer Medicine Service
`Memorial Sloan-Kctterll-lg
`Cancer Cutler
`New York, New York
`
`Update 0Il the
`ement of
`Manag
`Advanced Breast Cancer
`
`ABtS'l'RAC|'
`timer uittlr trunpariag lingll-agent vs tolttbitunitn ilurllpy in attra-
`surnebrear eaneasuggcstlltltl it may be kinda re¢t7tut'dertIteDzl.t‘zj'tImt
`rautbinatianelulrrotltrrttpy itllugaldxtanrltrrtlafrr-mrntznt. Baudon the
`lt'trtt'lai rnttdatttt'u4m‘al data available to date, ltlgh-dart elutvlallulapy
`with mm-allrescue slitrttld notbe vinudtr: "flute-I1]-di:an"trrmuent
`fUrBfldJldfl:¢dtfi‘tIllflDdlklllHDEIHMDntUllIIlI£Wnl£flnIrHlIital
`trials. Recent lriak have Lapland Ill: npnlnttl daring and Irltetinling uf
`Ill: rttrttm. rtr it-rllrtt the pns.n'ttl.e ml: trithere rrgenu in enntltituuan
`nginun: Capecitnblae (Xdnda), II new ornljlttvmpyritaidine, appear: to
`be Ctvlipulubk in afielaey M CMF feyehpltalpbaltidg nldhoflullt. and
`fluamrtrrtritt andpuetiniart rm tuggurptrsnbte rynerp between this
`agtnnutrmte lrtnrntt ottterprtrrrrtring rrgertts rrrtrturttrd; ittelnde lipo-
`rant:-¢ttr1z,psultr«teddtmtrltlu'ct'tt(I'LCD-99).tuttltuunacaqfttgmlittlittg
`rr dliullrlz tlrrnrnn/ttmtrr nattaeltznalautibndyla daatantblcin molezulru;
`MTA (LYZJISIO. n nttrllitargrlcd tattttfolttu; and mwtbth-fat, ll hund-
`rprcrrrutt imam‘: ntetallnprultirtase
`ratruuryut (Nttlmdex) re-
`rrtrtlrtrtlte masti-tpurtantaormunalagenghwuvannkratsgnunnd
`relecfiu emugrn teequnrmadulttrats (SEKMs)uqpmvida nllcnunlives.
`itepalenlinlmlee/newuuutalmeilhtlilarxasfirsl-Iinehonwnalegcnlt
`requthxfttrlllzrand}. Finally, thepossibletylerg bmrun Dnxltrzttnmb
`(llareplinj. ll mcnnrbitttml Jtttntmiudttttrlncbtnalnrtlibtady Inthe HER-
`Z/nutprotein, anaparliruellrnotl it tringrmdtetdia rm: elrntwrrirttr.
`
`
`
`have heen eytlcrphospttarnitle (Cytnx-
`au.Nl:usar m&l.lImItXIl£.lltutmiirat:il.
`dnxotltb
`and, rrttne recently. ilk
`taxancs. When the disease progresses
`
`flrrilier.
`iintelhili: (N:tt:lbin£) and
`other v ca alkaloids. mitomycitt
`(Mutatnyrin). lniloxatltmne (Navan-
`tmttel. xetttdlaltitt: (Gemut). alwa-
`tide. and eisplatirt (Plalittnl) represent
`sotneafthe other frlaqttczltly used cyw
`lottie drugs.
`MAY I999 - DNCOLDGY
`
`
`
`64']
`
`sible and to extend ilic tiunlinnol'Iliglt-
`quality lire.
`Metastatic breast cancer is mntlerv
`alely sensitive in chemotherapy. with
`155 in 40% of patients achieving a
`partial or. less commonly. rotttplul: re-
`sponse ID singlmgent therapy; the du-
`rativn of such responses averages 6
`tmtttl-is [3] Historically, the IIKISK colu-
`tttunly used cyltrtottic agents in Ilium!»-
`agetnent
`til’ metastatic breast callner
`
`nxlst cancer is the l'l'Il\§I frequent
`
`diagnttsetl cancer in Ameri-
`can wolnett. andtlte second must
`rarnttlottcalisclal‘cant:¢xdc.1th.[I] Over
`the past several decades, there nas been
`a fairly steady increase in the incidence
`ufthl: disease Epidcrniologic data frorn
`the United states analylerl
`llciweeli
`1985 and |990indit'a.tc lltal ll: Iileiittie
`risk or dcvcluping blast arrcer is
`l2.2‘£.or, stated in another way. trtte in
`eight\ir'fllll£n will develtypthe disease at
`some paint rlltritlg her lil'e.(2)
`Allhnugh approximately soar at
`brcastcancer patients present with dis-
`ease limited to the breast artdlor axil-
`lary lymph nodts. allxlast hall of these
`patil:nLs later develop tttelastatic dis-
`ease and eventually succumb to it. Met-
`aslattc breast cancer represents a
`historically incurable coltdilitlii despite
`the judicious use at vrlrintis honnortiil
`ttlallipllltiimls. as well as surgical and
`ladiotaerapeuric intervetltinns, and the
`application of active cytotoxic dmrm
`ttterttpetttie agents for lIoflIIlnc~l’:fl'iic-
`lofy disease. For mtrsl patients with
`mrtaselti: disease. treatment provides
`only lempclrary control of cancer
`gmwllt. Outside etetperinrerttal proto-
`ralt, L‘i€ goals at lrlanagemctll. there-
`fore, at: in palliale syrnplnms with IS
`littlc lludlmenl-l'e|aL2d toxicity as pos-
`DIKi1t tutu tupiuollhis mink lax wrinltal
`trvrnttrtstusemt,-herrnaerrnaarsqecapia
`tqrtrralxatnurnltertetzttirethztaflrp-=t>=x=a=r
`sx|1yl'xltepidtntt:Capyn;lttC|earIlxeC:ttv
`ru, :22 tttrsewopd urive. D:n\a1.MA olm.
`Srhxily ISSN 0890-90“. For irrrtttr inlprrn.-
`Llntl. (mun ilk EEC ill S93-TSILBIH, Write
`publisher (er hulk dttauthina.
`
`

`
`;_____:_
`Table 1
`Randomized Trlals at High-Dose CllernnlherapyIAulolognua Sum-cell Rascuu (HDCIASCH)
`for Meraalaltic Breast Cancer
`Trial Number!
`5-null Sh-
`ram-I
`oou-pl-uan am
`Amuar
`Spanlnrll)
`rlocalscrl Amt
`Domtol Ann
`PET-01 rrnlaaelpnia
`CMF2CAF x 4-5-»
`cur/car a we _.
`wlmur 1937
`an(sranaanams.)
`sls (ram nasal
`Glnup. E006. swoca.
`HDCJASCH: mob
`cur x 2 yr
`HCCTG)
`om Ulliversity
`am v 24 -0
`to
`- AFM » 24-.
`HDCIASCHICEP
`Allzlavsfl can
`r-sense
`can A -.
`ran
`CEF x I:
`nnculsca: GT
`NCIC
`Aura-la
`ConliIlmaA(lnflosafirl'll\) Mn
`Hnaascrl.
`mill (9 cycles)
`GMICh x 2
`_a
`mamas non zuiumu J Jll-'51! cusan-190(Jl:aoaao9. 1935.
`A : Aaklamyfin: Am . Aananansn mmmacl, mmormam out = cycnal-ow-rr-me. Mu-nudn. haarvl-tan‘: nap . cyt*'l1'-Imanvuv. new in»
`nusllna), rauulln;ctr aG1:|rlvMn0DsatIv*d0.|!uavl7llralI:'tCMi .G ncnoauara. anon-ma; ulncla nC , ins
`.r.Im=fl-‘III. Ems = small Uswnlmouotnvvamwz
`raumnm. aalmpurln; an Cv=hli-savanna. lNdapn.CVCn -Cydlaulllasamllnldmlhfllipl.
`_
`"gym,mama“y,.,..n...a....,nclc.u;ln.ulcy=ulumnuml:maa;rar.n-aaeularrasannumnrwsease-sod-n
`pl-urlcals-v-tvalinrsuuaalla-.raaaaaaaanmnamnuunlhiuaucu-aacsluoa-sulnmmawunvfi-vnzrxatual
`‘nailum I. law
`
`On lllebasis aflh: lil'ni|r.dd:lI1 avail-
`Tamra:
`able lo dal: [mm rarldllmlzul. Pfl!5P=:-
`liv: mall. high-dost cllcmnlllerapy
`Ratlwltllzaad Trials nl Single-Aqlml Taxams in Mataamlc
`cannot ya la: considmd "slal:~ol»lJ'l:-
`Brian Cancer: Dose and Adnllnltllratlnn Schedule
`an" lxnlnlanl for advautad hrcaar can-
`mu
`ldrlllnllltlflntl
`r-mapanaa
`cumdummhaofianal nnlyloplaticuls
`sdsuaululh)
`natal‘!-)
`sum
`(HEMP)
`in Ill: scllingofcllllical lrl_als. The final
`results olscch large pmpmlva lrials
`Panlllarel
`are eagerly awaited (Tlllllu l).
`291'.ax
`smsma
`lfmulliagcnl cltcmolhcrapy anddose
`escalalion pm»: la be sllhuptimall in
`297-12']:
`cunrming n cmlsislunl svnlval advan-
`BMS07I
`tage in melaslali: breast canuzr. Mhni
`40%50'!-
`sltalcglu must be plnsnad. "nus: in-
`Nsaawa-ea '
`clllrle lilzdcvclopl-rrzllt of newer active
`drugs. or me allplatrlliml nf diffcrtnl
`2m2!?»22%
`was 9:42
`ailcmalivcs, for unmplc, biological
`lhcrapits.
`29%
`Ilaxamulflflanné
`23%
`The rllullrs, it: paclilaxcl and done-
`ml
`NA
`In
`larzl. are a rtlat cly ncw arldiliorl na
`mo mg!-ni
`m
`ma chnlunliluupculic alscual against
`75 rrlwltl’
`lzreasl canccr. Their mechanism of luc-
`?:_:_.
`liun inwolves ml: fnmlntion ofpalymrr
`lied microluisllles and their slahiliutlnrl
`ms-ualuu-lny-usandtzn;cAtt:a-cua:.a1uvunliGluaoa:la>Aac- u.n Amulwl
`cuvavcua~nua.ndbvuun;ns.naxlwlt=rtn:Aar:luhunanrnsl-aaalnnaa
`uuauanrrnlentnfin-nvuonevnnznraanv
`against me {areas that laid lo dcpaly-
`
`ian.Pmapclploll:cllzcl.1. as well
`'
`Is nntlallgingerli: actions, may also be
`clinically r¢l¢vznl.[l4.l51
`The lldnnnlrlaliorl nr optimal dos—
`mg and schcduling uflaxancs has been
`an impananl abjcclivc during their dc-
`
`Pvalun
`
`NS
`
`MAV I999 - Ducolnnv
`
`649
`
`veloplllanl. Wlril: ll»: clinical davclor
`lneall ol doczlaxal
`lurgaly invnlvui
`asillfllzladnultislrallnn scilndlllc (I-hour
`lniusicn) and a nannw mu mug; (60
`In 100 mym’), Ila: range of paclllaxal
`dual and sclledulcs has Ia-an blunder
`(varying [mm 80 la Z50 mg/tn‘ it-fund
`am I hour weekly to 3-, 2.4., at can
`96-hour lfl'|Bi0fE ulry 3 Weeks)-
`
`with metastatic hrr.-lsl umcr.r.[2l)
`Anmlturrlndumizedclinical trial led
`by M. D. Anderson (‘Alma Center dc-
`tlaclcd no significant diffarncc in ob
`jccliva raslmscs or survival wilh
`padltaul al cnhu 140 alyne via a
`96-hour infusion nr 250 rrlylrl’ via I
`3-nan. irtI'lniCI'l—Ill: maximally toler-
`ated rinses II drug sdmdull-_s.[12]
`Two mm ulnls have addressed op-
`nnnal paclilaxtzl sclltduling. Th: l'IlI—
`dnlrliaad. Bristol—My'=rs Squibb (EMS)
`07l trial. in winch women wnll unna-
`cliniul llnln luv: suycsuad lluu ul:
`E‘.-“w‘°pIifl|l-ld Dust and Sdmduh-—Pr=
`sultic breast cancer were tzulad will:
`lfumlioll orpadiraxzl expnsum may be
`palclluxcl (I 75 IIIgIll|’l inflfldl our ex-
`mam ilnponanl lllalldou fur the cylcv
`mu 3 In 24hours. allowing forinInlpz—
`mic ncfivily of this dmg. Dqaamlng
`Utnl dose escalation as lnlalalcd. was
`on Its: duration of cxposurz. cellular
`cymtuxicily can In Ichlavcd at rah-
`cunductad lurgdy in Ellaopc. Cllnllfla.
`and Israel. The two mum did llol dil-
`uvaly lmv cunccnllalilans nflnanlilaxcl.
`raalgninr-anrly Vlilh rupulmruporuc
`nu ma ordu nmol nM.[ls,l7y That
`rall-.5 (29% and 32%. ruspl-.:Iiv:ly).f23]
`nun-nan ofmlpmur: an It an impur-
`sirnllanmlls weraabtzinedby Na.
`unl elernenl in the Clilliuli activity of
`Llnnlll Surgical Adjuvant Ernst and
`pacliuxel in; also hlzn liznlanstnled
`Bowel Pmjtct (NSABP) trial B-26. in
`by the aaivlry of pnalnngm 96-hour
`llris trial, lupnnsc mu Int paclilaael
`mnrilluuus infulliurls in mm: patients
`with mztarlazichraucancusoon alter
`rm rrlyrrl‘) inrnsan lava cillw 3 nr 24
`hours war: was and soar. respuuvaly.
`-nan disuse pnagnsua during tllnnu
`suggl-sung mar in: mm: rnyalasnppma
`illlusions cl me l-1nlg.{l!,l9]}lnwev:r,
`ve Z3-hutlrscltaiulctlozs not rzsulx in
`Ill: Idnlillisniliull of9&hmlr continu-
`
`ous '
`inns nf paplimzl ilnpoacs u
`u significant illlprnvemclll im nlllclimt
`I‘.¢|'lllll lncnrlvcniclme furiuxll Lite Clin-
`in Ill: pallialivz s:lIl'n,g.['ld] ‘I'll: inclu-
`sion of patients willl stage III]! disease
`ic and palizm.
`punly glplaillsdlzltighzrlzsporlsepllr
`Mlny clinilal trials hive addrussnd
`lllzlma ufbolll Iheoptirrlal dosing and
`partinrls in din NSABP B-26 trial,
`as Cflmpiflfl In the nforcmcnliouerl
`uzllalluling of ill: inane: (hill: 1).
`suldiu,
`Widlltgatdlndosingtllctuultsttfa.
`nndomiled trial of paclilaxal floss of
`n Weekly Adnu'n1strallnn—AM:thcr
`I35 vs I75 rnglln’ on a 3-hour schzdule
`nlcrhod tn pmvirk urandni cumula-
`in pmrmln! wnrllal with maaslalic
`liv: drug expoaum is riequenl upti-
`bltlil cancer revealed no major dil'l':r-
`:llus'lnrespunscl1l:s(2‘2‘laand29‘l:.
`live lung adrntllistl-atinn. such as by a
`wazkly scllzdule. Weakly dosing of
`lupecttvaly) ur lnanian slllrvivul dun-
`Iinns (I01 and IL7 mnnlhs. lupu-
`pacllmcl viaa I-ltmll ittfusicllltltashun
`demmlsuuladmbeawell-lnlaralall. fea-
`Ilvzly). Prnyaaalanraae survival was
`sihle administration xcIlcdul:.[ZS]
`slighlly longerwilll me I75-mglnfdosc
`than with Lb:
`llzwer dl:l§¢ (Q2 vs I
`Weekly afltrllnislnliurl ofpaclilual is
`both dnS:»'tn.l.n1sz and dnsodcllsa hlll
`lmulhs‘. P = .01). howcver.[20)
`'
`also has a (avurabvc lmizily pmfile and
`In Ill: Cltltzr and lnukernil Group
`a rcmarlrahlz angle: or nuivity in ‘pa.
`B (CALEB) trial 9342 rzpnnxal al the
`Iienls willr lnaaslalic brusl calllzr.
`masses mun; 4S0pu.i:ms Wu:
`landarlliud In ruczivz I75-. Ill}. or
`In nur upanannear Mama:-ial Sloan-
`Kutering Cmcu Canlcr. the uvernll r¢~
`25mnyrn1 dnszs of paclilual an a
`'.Hlmlr sclluhtlc. ‘I'll: Ihra: gruups did
`spins: ralc In a wmkly aalninlsnalinn
`notdjfiu willl rt-span to mptlnsc r-all-.s
`sckleduk was 53% (95% confidalqc in-
`larval [Cl]. 34% ID 725:), which mm-
`or survival. but Ill: highzr dusts war:
`pales favnrllbly with Ih: activity llulad
`asmciatali with gluru lmlicily, partic-
`for 3.. 2+. and 96-hour lcgintuu. in
`ularly peripheral rleumpathy (26% rate
`mutual lo mas: olllar lcgilllans how-
`oignda 3 evcnts). ‘l'hr.rc data pnaviaad
`littlc camp-.llin3 evidmc: In mppnfl
`cvcl-. myclnsuppnassiorl was luslgrllfr
`pxlitaxzl 3-hour innnlnn dating uf
`can with nearly paaluml_ nn mall:
`neurmpgniu was anmllnlned, and an
`gruzcr lhan I75 mgll-n’
`in woman
`650
`ollcouxlv - vot.uuEll - NUMBERS
`
`palicnl rrquimd ncnlarnpaieuc y'DWUl
`fnctursuppon.
`A possihl: elplulaliun for the norm
`ull:nup|' g or am, a-lam, from my»
`clululuclly in wet-ltly 1-lluur puclilaxel
`my be round in the pnamraaulynaanic
`ohsarvauon lhzl. wiul
`lhis schedule,
`plasma paclilaxcl mlrcnlmlions n-main
`Ibuv: 0. I umnl/L fr: n relarjvcly brief
`period nllnr arlnscol loo mg/lI1'd:llv.
`and um I lnnn, Huizing :1 al laava. in
`fact. previously rv.-punad mat to achieve
`an arm. do: in: fmm basclmz utaaolura
`nculmphll count. plasma paclituel eon-
`ccnlnltiml would new In rcnlaln Ibovc
`ua: Illreshola coltnnlralion or 0.1
`tutlalll. iorllpprmlimalcly 20 hours.|26]
`Tllls. cnrlsidcnad Ingelhzr with the cy-
`allc kirlzucs of nautroph-| mama-
`lion, may explain me relative lack of
`myclnsilpprcssinn.
`I Pllt:lilaxclrCont:Ining Cnmhina.
`Iiarl llqgnaa-n.s—c.iv=n me man: pub
`vinusly ralstd about tombinatinn
`chclnulhcrapy for mclaslauc |srmsl:m—
`cut. :1 lb: was nsco ma--lng, mean
`an! prcscnlulla phaslt llsnulyail-um at
`delzl-mining the rcspnllsc rate and safe-
`ly at a cnlnbinalion nr paclitalxzl (so
`rnyanllnlnszu war I nun), llIIuruu-
`l-acil (425 Ill m‘), am lananvann (20
`
`l1|gIm’)ild.l1I ml wzckly as fits!-
`Iiu: llllxupy in palicnls with mu.-lsralil:
`hrulsl c:lxrc:r.|27) Full dnsas could be ‘
`rldmlnisllrl-A inlh: lnuttll wmlr ta unly
`63% at’ parinnls. plirltalily due In diar-
`rhca and ngulropuliaz a ‘1 week on, l
`weak nfl" rcgimcrl subs:-qucnfly mer-
`.-anae this problem.
`Thirty pnliznls war: l:va|u:lIt:ll: The
`overall rcspollsc rat: was 471.. with
`I0‘l>cornp|cIz rcrrlissiuns and 37% pan
`lial remissions. This Iclivily is compl-
`rahlz In ulllzr rzgimans |ll similar
`palianls.
`Annular abstrscl prrsulllzd al ASCO
`1993 lzlnrlnl nu ma rsulls cl a ran-
`dolnlzd lrialcamparillg paalnaxcl plus
`lusnlinlrnnt, an antlll-Xpyrazulc in
`clinical dgvtlupmcnlv with slruulural
`simllalilics to both linxaruhirln and mi-
`lnxmltml-la. vs paclilalcl alnn:.|2Hl ln
`148 ynlicntl. a rnsponsc rate ol 54%
`walnmxd withlhccnnlbillation vs I51:
`willl paclitallel alum: (F < .Cl)l). Pm—
`gxasiiull-fro: survival wlls significantly
`supcnor with lhecolltbinllloll regimen
`as well.
`Tullicily was also higllcrvvltll paclr
`|l|.€I plus losoxanlmtle. llowem. Pa-
`
`,
`
`Astrazeneca Ex. 2010 p. 2
`
`ill
`
`I75 rnwl~n=.
`-35 n-Wm‘
`r75. "lame
`250 nI9’Irr*
`:75 nlghni
`Zilllrlym’
`zsomlvml
`I40 rnD'Irl'
`zsa mafm‘
`
`MDACC
`'
`
`Wa
`
`_
`
`

`
`tlellls treat.-.d unit nit i:umbin:ln'utt leg-
`itttzn had I 66% incidence ofgtaliz 3-4
`ncutlopmia, Vs a tale til’ 31% wldl
`paclitanel altme. and two cases at can-
`gcslive litart tailurt occurred wittt III:
`
`cottthinatiull. vs tint case witrt pacll
`:1 alone. Analysis of sltrvlv-al aw is
`lmtger follow-up, but dies: dataare cer-
`tainly pmvtxative, if not surprising in
`light of the ECOG I193 results with
`prclintitrl plus tluxol'ublciIt.[7]
`Down-tt
`Regarding drtctttxtl, Loefllex at al
`reported their experience with weekly
`infusions in stage DI breast cancer pa-
`|ll:lI5-I29] Dose: were escalated in in-
`ttemenli of S m§'nt’ from 30 tn IS
`mg/m‘v~'eelt.Iy X 6 \Vl|lt a mum mtnli.
`The nvetall response we was 10%. Will!
`15% complete remissivns and 35% par-
`tial remissions: 3S%l1l'pal.iu|ls hadsta-
`bl: disease. Moreover, three out offive
`patients with a ltlstnry rt!pnor pacliuul-
`tllhulpy rt.-spmtdrduidot:etaxet.'l'itese
`invutigalnrs nbscrved that weekly tinc-
`etaitel has activity in Cltm‘KtlIt:l'i|)y-Ql'G-
`treated breastcnnur that is mmparahlr.
`to I00 tnglin‘ of tlocetuel every 3
`weeks, but with apparently less grade
`3-: lcuknpcrtll.
`Anttttter ASCD Presentation by
`Syisstrametaltocusedonapttaselll
`tn'tt tnnr cotnpand dtxttntttl (too my
`rrr')et'fl'v 3 weeks to ntetltntrexate fill)
`tttytn‘) tilts lluolvuncil (G00 mrlm’
`on days I and 8) every 3 weeks (MF
`regiment in 199 patients with antltracy-
`clirlmrulslant breast CIlt(‘£I'.[30] The
`overall response ml: (partial and com-
`pleut) was 42% in the dacetaxel arm
`and I992 in the MF and (P < .00|);
`rnedinn lime to prvgressian was 6
`months in the docntaxel your: and J
`mounts in the ME gmup (P = .006)
`-Theseresults thus dzrncnstnterl Illa su-
`petindty ofsingle-ageltt docetnztel ever
`MP for pnuents with ttntttrat:ycIirte»re-
`txlslllnl tnetaslatic breast eitucer.
`nztzrcdrrtttr
`Capecilahine
`Cnttndzt-ing tt£\N:ldrugslorddvarteel
`lttust uncct. one of the most interesting
`.-tgcnu iscitptciuhirlt (x=ttida).opecit—
`ahine is I ttovd. oral, selectively tumul-
`actititllcdfltntwpytinudutccm-lgartuletlnt
`has shown pmmisitt; azlivily in latest
`and calm cancers during phase: I and II
`Evaltlaxlhlts. Tint agent is sequentially
`
`Stnlchlm
`
` l
`
`N
`tJ\
`0 N
`
`I
`
`F
`
`nit:
`
`WI
`
`on
`no
`capuunin.
`
`F
`
`-
`
`.,
`lN
`M
`5HJ
`
`
`
`Figure 1: Chulllnal Slnttmtrl ind mcttartirut rd Aflinn at cttpet:ndnin_o—
`5‘-DFGR = 5'-Dzotty-5l1uorocyti¢ine' 5'-DFUR = 5’-_Daoxy-5-lluuruundtne;
`a'THdF3se = Tnymidine pltosphotytase: 5-Ft] = Fitomurncll
`
`cttrrtverted to lluomuncil by Hum en-
`zylltls lncalnl lll the liver and within
`tumors. with the linal conversion II‘-F "1
`lltmtt:an1cil(xa]y1t:dl1yt]tylnidiJE|i|os~
`pltarylase, wlridt is {mind pretamlially
`inbtmtcattnaurltsasrnmparedtosdr-
`mttttding ttotttlzl has tissues [figure 1)-
`An instinct tmtntrd by Blunt et al
`at the i998 ASCO meeting descnhcd:
`,pltase!llrialolIwit:c-drtily ttmltzpeclk
`abitte (2,510 mg/lll'IEl) given (or 2
`waits, folluwui by a l-week rut peri-
`od, and repeated in 3-tin-.=lr cycles,
`among patients with parJll21:l-t:f|'zI:-
`tnry metastatic breast can:cr.[3l] A to-
`lal cf 16] patients were enrolled by 24
`centcts; patients had received at least
`two but no more than titre: print che-
`tttntltuzpetttit: regimens. one of which
`cunutined paeliluel as treatment for
`irietutatir: rttsuse.
`The primary study end point wls
`tuinnr response in patients wiut ina-
`suntale disuse 11:: response rate was
`2095, median tzspcnsc dut-ntinn was in
`rnundtt, nnd rltalialt survival via! its
`months. Moreover. in patients with
`baseline pain > 20 Il|lI1 on a visual ana-
`log wilt. 47% showed :tsignifil'2nl.iln-
`pruvrntutt in pain. Diarrhea (mi) and
`
`‘
`
`hand-font syndrome (10%) were in:
`only ltealtmlll-tallied adverse events
`Ihllocrtmed willtaglidzlor-1 inlet!-
`sity tn 2 low. nl patiatu. Alopmia did
`not occur and fllyddsttpprestion was
`minimal; lltete Wu tw ueaItttutt-relu-
`ed mnnality.
`.
`Glvat these data und the hisltarital
`context urine use of continuous inna-
`vettous ittlttsintls uf flltt1'mur:til as a
`salvage ttlenpy for inetastatie breast
`cancer. capmvabine was approved by
`the FDA [at us: in patients with panti-
`taltel-tefnetury metastatic breast san-
`uer in the spring (it 1998. In sttrntnary.
`upecilifitt can be considered an ac-
`tive drug in llt: Lrenttnent_ol pactitaxeI-
`tuftacrnry advanced ltteul cancer with
`I rrlntively favorable rulticity profile.
`. unrrtttiblne vs outer Agents-—A
`s¢:ntd:lt%l t'ep0rlEdIKASCO 1991
`ml the results cl a randomized
`phase II trial at uptcilnliitlc vs qiclo
`phtqitumid=.nl:I.lI>uexatz.andlItnmu-
`t-dcil (CMF) Is lit:-line dntnmlufllfl
`for advanced breast cancer in Wnllllfl
`>5Syeatsuld(lnediarlagpinbr:mgttttt;xs
`69 yuts).[32]
`was gjvrzl
`orally at ndmageollilll tnym’t'd fut
`MAY I999 - ONCOLOGY
`651
`
`laxanfi, was evnluatexl in Five mouse
`2 weeks. lalbwed by I want nd ttst,
`IndCMFvrds Idhtlvtisletrrl ll|ll1VlElKX|&
`ltenogralt lztndzls nlltun-l.-lit breast car-
`trittnntzt ce|Ii.[34) Wltlle LII: oumttiua.
`lyuttdzy l every2l ttt28l1:ys
`A |DL‘|l bf 95 watrlett were rattclutw
`lion of fluotuurucil and lattaues
`iwl, Response HIE were 254li'in the
`dettlutlstrdlul only "additive clficacy.
`trcatrnent with l1pC€lH-bin: and mem-
`Eimcitlllillblrelted patienu and I64}
`in the EMF nzipients. and time ruptu-
`attzs slluilell synergy and produced tI.|—
`gretsinn was 132 days with eapecitab-
`mm regression in same ltenugrafl
`ntudzls. In fact. the tairanes tttcnasad
`in: V5 94 days wittt CMF.
`Regarding lnxicily. grade 3.4 t-litti.
`Illt: Itlutm levels ofrttytnidin: |1lIm|)lt0-
`rylisa: my rant- ll) tigtntald within 4 to
`aladvasttvtntsurttrtptntrdnyus.
`ID days fullntving the sitigle adminis-
`of patients receiving capecitattine and
`Llilinll; (ll: ttearrnrnr did not increase
`20-1. psiitittt mind with cum. ‘nit
`llll: mmlsc nnlyrnz levels in ttnnnal tit.
`diffwmce batman the two gt-tttps was
`slfi fttttnstirle andlivt-.t).lI1weveI'.Sim¢
`due primarily tn llutd-{not syndmme
`(tail. Vs 0%) and diarrhea (sat vs 35).
`ttttnml Lhymidine pltospitarylau lev-
`On the ntller hand, gnde 34 heimtr>-
`elx correlate with in viva suscepdbilily
`In Capctllalline, it is prtstiiilr that lh:
`logic toxicity occurred mute frequent-
`taxarles may exllmlec llte eflicacy of
`Iy with CMF (47%) dtun with unn-
`citslitiigrzmtt
`capncitntiint lty tlpllgtlllling int en-
`Ovenll. within tlte constraints im-
`zyme in hllrllzll tE.l'lLE1 rtlls.
`pt-rttd by relatively small sample tins.
`R.
`.Qw
`it appears that hmne-Imntl ll'tflml.lcfl-
`py trim caperitatiint appears in have at
`for newer
`The continued szartzlt
`ltI!ll.‘DmpIl1bI:ti‘fit'2cymCM.FuIl'II-
`hilhfilln dmpy in tin; nldu plllnnl
`agents for cuttlml nfdiselsc and pallia-
`pnpttlulon.
`tinn Dl Symptullls in ntttastatic blelsl
`t-ant-.er has alsn led totlte manipulation
`Finally.
`in I lltllltinettlnr trial pre-
`sanai by O'Rcillyet al. Ll'tE activity or
`or ill: mare conventional drugs In at to
`capesitalrille was mrnpared tn that M
`achieve rqttltrzlenl or pnssitily gtzllzr
`luelinxcl
`l1I palierls with adunntzul
`activity with thenzased toxicity.
`brat cancer whose disuse had pm-
`gttsted following pt-int anlltmtzyclitte
`Llpttsomxl Du:urtt.tzlt:itt
`llIc.l1py.[33] tn Ihis study, inn sched-
`One prttntising agent in this respect
`ules rtt raperiuttint was planned:
`is lllxlsnmz-crltzpsulzleti dmttirntiir.-irt
`rru: n99) A phase ut trial zepolled
`(l)2,5l0 mglm‘Mfar I4days. fiulluwul
`IIASCO l99$evttltt:ttedil5 usevscun-
`by l week of IE.'il’. at (2) n onntinutnts
`ttentional ctnxdr-ulztctn. limit at adose nf
`daily scltedule tit l,nt ntgttnvd mt
`15 t1|gIltt':vt:ry 3 tvrt-_tts.[3si'tttis trial
`continuous an-n dfeapecilahine was dis-
`ctttttinuui. hrwitever, after twn patients
`randnrnized 69 patients who were strat-
`waecnrolled.[persmalcotnnmnir.:tiun,
`ifted an Ill: intis in print exposure in
`
`Dr. Faltln arnutrttt‘, Rnche, lite- Fat-
`doxtntttiici
`Dttnl-lg ttit trial. patients
`ruuy 1999]) Pnclilaxel was adl1tinis-
`ultdctwcnl saint vrtnrir.-nlogtttpity tit
`cumulative doses of SUJ. M1). and 500
`teted II a change of I75 mglrn‘ on
`day I ofeach 3-week cycle.
`ntytni unit tttrn every cycle thztnflu
`Patients were removed rmrn the study
`With ll evaluable palienu, the in-
`Izrnlittcnl schedule of npeciulzine
`if llefl-tllznlllitlltnr ejection fraction
`yielded n 36'} response rate. as mm-
`(LVEF)du:linalt7y2209tl'tunttlt:
`hascllne vnttteottltis traltte tvatzsmn
`Plmd with a Ell: rate with palzlituel.
`Dr iiy 2 mat lnnn nastlint (it<smi,3_
`Median little topmgrssion was92 days
`on Ill: inlet-tniuent capecitzbine sched-
`at ifcnttgesxive hurl failuttdevelutzd.
`ule Ind 95 days on paelitaxel. Grade I!-
`Response rates were 335 in nit
`TLC D-99 arm and 295 in the doxuru.
`4 events were reported in 22% at
`bicin trtn. Congestive titan tiilttr: tit-
`pati-its ltuled with tflpclilnhlltc tnd
`53% givttt pxliuul.
`Veltlped in dtnte ptitirnts (4-it) truutd
`with duxorultitin but in nan: Df thus:
`I Clpeeiutltitte in Ctttnltittlllort
`given TLC D-99. Alia. TLC D—99
`gtnrntly pI0dII£:d less entesis. stoma.
`Regitttens—ln a t:le'tmnI prctlinical
`Jnplttse study. lheeflieney t-rft:3pet:it-
`titis. fever‘ and infection, suggesting
`Ibtne and llttaroul-tril in enmbinatmn
`tint it may as tllactlvk as free damni-
`witit ttdtrr rymrttntit agents. including
`lticitl but pertups sarrr.
`652
`oNcm.oav - vuu.iM£ ll - Numatrs
`
`A Naval ltntttnttoconjttgltle
`Toleltcr el al ttrsct-that I! phase ii
`nutdtintiud trial in wttiut .-r nnvel Im.
`trluttpcunjugate linking it chimeric hu-
`lltnnltt-louse monoclnnnl antibody to
`-Wm-inlatniy night floxotubicin rnolt.
`cules wascnnlpared to dmarubit.-trt.(3s|
`This antibody is directed against the
`Lewis: antigen, wltidi is expressed it.
`75% at all breast tmluzrs but has limit-
`at expression in rlnnnal tissues, has
`shmvn promising attlilutttor activity in
`plaillnlcal lclluglin Iluxlels.
`A rrttal pf 75 patients with metastat-
`ir: hrenstrzrtet-.r entered mistrial. There
`was one partial rernissian in die in
`patients (1%) on the mmunocottjugnle
`amt. sltnwittg mztti
`clinical at:tivi y is
`llrnltr-d. Also, two patients in this amt
`developed grade :4 toxicity with ll:m~
`nrrrtagit: gartrins,possibly reflecting the
`fact that me Lewis’ antigenunlurtunate-
`lyis alsoeltprttued nntomeganmintes
`Lina] l|'\lICDSI.l cells.
`New, Multitargrted Anrifolnu
`MTA (Lv23lst4) it a new. rnulti
`tztgetnt arltifclalc that inhibits tttyrnidy-
`lat:tynmam and otherfolaledeputdettl
`enzymes. itteltlding diltydrufolate reduc-
`use and glytzinamide ribonncleotide
`furutylu-n5l':t1s:. II has potent ultim-
`mtv activity in vitrti and in vivo and
`produced respunsts in phase I trials.
`A plus: it study that evaluated lite
`activity or MTA in 33 p:li:ltlS'wilh
`lncally tezttnenl rtr mrzrzstntic blfzsl
`czttuetwlspxzsettledattlle l998 ASCO
`tneeung.[31] Of the 38 patients, 8 were
`ciii.-tntttiteraiiy-—ntti'vt,
`I4 itad rec Wed
`nrnnvantcitci-rttitltrt-tpy, | I itnd received
`chettmtlterzpy for metastatic disease,
`and 5 patients‘ had had built MTA was
`illnlltislerul at ll dtrszge ttitsoo trig/nil
`every tl ttuys.
`ttespnnrrs were documented in it
`palizltl-5 (at-as). want t complete unit to
`panittl temissiorts. 01 the l I patients
`Who lupunded. 5 had mctivnd prior
`tanttt or anthrzcytlln: dterttpy. Medi-
`ul dtntitiun titresponse was 3+ tnnntnt.
`Overall. 135 cycles of MT/K were {lt-
`lilrelui with 28 date reductiuns and I6
`delays. Reamns [at n:1ur:tiol-is includ-
`all rm-rrupertin (39%). rnucrtsitis (taut),
`and tmttsstminase elevation (23%).
`Grade 2-3 notttletnatulngie wxlcities
`ittchtded tnltcositis (14%), nausea and
`vnnliting (39%), and lrttmaminase ele-
`vatintt (tam Also, I grade 2 skin rttsn
`dmlopcd in mi of patients, a grade 3
`
`Astrazeneca Ex. 2010 p. 3
`
`

`
`the patients
`advantages However,
`who received concomitant
`l|rllt:lx-
`lien Ind gore:-elin cltperienced more
`tttx‘tc'tty.[50]
`o ‘]'nmtrn'l¢n Rts.islnmne~—UrllorI-u-
`naiely. blunt cancer in most patients
`will eventually become resistant
`to
`tamoxifen. Tantnxifut resistance is not
`fully understood. None ofthe proposed
`ntecllznistm. such as the cnttergcnce of
`tamoxifen-dependent cell
`lines and
`loss or mutations olthe ER. its inne-
`lio