DO|:10.1158/1078-O432.CCR-O4-1402
`
`Clinical Cancer
`Research
`
`Approval Summary : Docetaxel in Combination with
`Prednisone for the Treatment of Androgen-Independent
`Hormone-Refractory Prostate Cancer
`
`Ramzi Dagher, Ning Li, Sophia Abraham, et al.
`
`Clin Cancer Res 2004;10:8147—8151. Published online December 28, 2004.
`
`U pdated Version
`
`Access the most recent version ofthis article at:
`doi:10.1158/1078—0432.CCR-04-1402
`
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`Downloaded from clincancerres.aacrjourna|s.org on October 25, 2011
`Copyright © 2004 American Association for Cancer Research
`
`CabR°f°°°2513
`
`AVENTIS EXHIBIT 2216
`Mylan v. Aventis IPR2016-00712
`
`

`
`UOlITU.‘1‘ 58?‘ U78—0?I32.CCR—0?l—14D‘2
`
`Vol. 10, 8147—815‘I, December 15, 2C-W4
`
`Clinical‘Cancer Research 8117
`
`}'C
`
`
`
`Uiviswn of oncology Drug Products, Lenter for Drug Evaluation and
`Research United States Food and Druo Administration. Rockville.
`
`Maryland
`
` j
`Purpose: Docetaxel, a taxane previously approved for
`
`IN—TRODUC'H9N
`
`Docetaxel r’TaxoLere Aventis Pharmaceuticals BridgeWa-
`
`
`u
`..
`.
`on
`—
`up.
`nu
`-
`- any
`--
`-
`-
`
`
`promotes the assembly or tubulin into stable microtuoules.
`crotubules bundles without normal fionctioo are '"
`mitosis is inhibited. Docetaxel has been previously approVed‘by
`
`theL.nitecll' S.ta.tesEh mdDn1g '' ’
`
`locally advanced tn"I1Je‘taslatit:‘b1'easL cancer after aI1i:l1Icu:ycli'I1B
`
` eeHMg cancer, was approved by the United States Food and Drug
`
`e.&dm
`prednlsone for the treatment of metastatlc androgen-1nde-
`ep
`of this summarv is to review the database supporting this
`
`
`
`. E
`
`combination with cisplatin for newly diagnosed locally ad-
`V' eell lung cancer.
`Atter clevelopinent of metastatic horn1one—retractory dis-
`ease,prostatecaacerisincuralale,wisl:1Bedians"ia~4Jxalof9to
`T2 months (1, 2). Flistoncally, no single agent or combination
`
`regimen’ hasshownasuorival bene.t'1.ti.n '
`mi rnnWm prednisrme Was
`F
`.
`.
`,
`F
`F
`F
`appmvedbvtlie EDAimmmflmVeum_mmt
`or bcdlh 3d‘a_n_C€d
`1-
`Emu had
`1
`i
`1
`hormonal
`therapy. This approval was based on results of a
`_
`pies prcdnisene to
`prednisone alone. A total ot 161 patients were randomized Ill
`thJ}strial,wlaichusedpalli-atiazerespoiasaasaprirnafi end-point
`[5, 4 . A second randomized [I181 of mitoxantrone plus hydro-
`
`cortisoneuezsrtshy ‘
`V
`_
`. _,
`eukemia Group B provided sumW
`and
`palliative effect (4\
` wn flor the TIXT q 3w arm over MT? q
`Mmemmsmmmm.9 mwmwemmmmgemmaam
`l1orn1one—refractorV prostate cancer either as a single dose every
` TXl‘
`3w‘eeksoraweei\lyreg'-rnen.P1=ostate—speeiiieantigen(P-815.3»
`declines. and radiographic responses in those patients with bi-
`
`xperimental Design: In a randomized. global study
` were
`
`compared with mitoxantrone + prednisone as follows: MTZ
`q3“’1'“1°m“t1°1'e 12mg 11331311
`1 11333
`p1e‘1"13°"e5
`-
`mgtwiceada_)ifiora_totalof_]_0c_}x;les;'IIXIq3w,
`
`EmghPfienHdafi+ &m
`atotalof1Dc;u;les;andT2fl‘qw,docetaxel30mg£m2days
`l,8,15,22,aIrd29every-6weei§s+prednlsone5mgtwice
`adayEo_ratotalot'5c:-tales.
`
`.l,7F.ljj.
`
`..E.
`
`nausea, sensory neuropafhy, fl_'u1d retention, alopecia, nail
` &figm
`Conclusions." Fliis report describes the Food and Drug
`
`
` '' " '
`H1-isfii-11312!-[9-191‘-O1¥'5ll0fEl
`combination therapy for hormone-refractory prostate can-
` ' asur—v-i-valbenetlt,
`
`uate
`
`TAX3Z7, a global multicenter trial, was designed to eval-
`ngg_
`- II -
`Il‘IIlI
`-
`'
`control armofrnrroxantrone plus prednisone.Tr1e design and
`fil1diIl0S._Df 'F‘ are outlined below
`
`Efixjxefi 7r1_~'u'o4,-_m;i_-mi 7rao;' mat
` mpEmw:RamzLN.DaghH,Umed
`H§F‘B—l‘58, 5658 Fis'l1e1s Bane, , Maryland
`ZU857. Phone: (F301) 827-1343; fax: r3U1) 59?1—L#F99; Email: dagnerr@
`cder.fda.gov.
`©2004 American Association for Cancer Research.
`
`PLAIN
`Patients were raeelenaieed to one of tlarc
`lollows:
`
`trcatrncnts as
`
`T—l=le rrcearrnenrplanisalsocmzl-inedir1Fi-g.l.
`q 3w.
`If-liroxanrrone l‘2 rngfm" intravenously (day 1)
`asa3“-mi.nu,tein£usione\zei:y“ldayspluspredr1isone5n;g
`or2dty“ovicedaityfot'tocycles.PredInsonecou1dbeco1Itinue‘d
`F
`F
`dfler C‘QiI"plE‘u'OD of 10 C¥d‘E‘S__
`11311‘ Cl 31”
`13055131151 -'5 11137111 11—"13Ve110‘151‘ (1137 1135
`a 1-hour infusion every 21 days plus prednisone 5 mg orally
`
`25’ 2611' C
`Copyright © 2004 American Assoclafionufor Cancer Research
`
`

`
`UO‘|:TU.‘l'T58TTU7B-U?F32.CCR-U4-1402
`
`81238
`
`azaomrr: for
`
`1'r:clfIflcI1t of PI'E}bl.':lLc L,':lITCr:I'
`
`I}im-gmxgi. "ii lnpfmt ]“i7 z;_2| weijss
`E.::hd.nj~mm‘_5_mIIg_]‘(} BLD
`in tag.-rag
`
`date of last assessment or on the cutoff date if the last contact
`
`had Efiku-H plaee
`Three simultaneous comparisons ot overall survival were
`®mwM1ammified
`multiplicity (I01-; TXT q 3w vemi.r control NITZ q 3w, T’l'>§‘.‘f q
`
`wrrw control1\d;EZq3w,orthet3.uopooledd.oceta;scel ueaunentgUupsvemo*iriecoritro1.”fT1e;n'o1x)ser1nonrlIral
`
`i'X|q3w,6r6‘1".+’5‘,aIrd
`loWs:Oomtr'rriex:l'I'XTg1“oups,Ett)4:
`'EX_Tqw 0.11175. Iheprimarvanalvsis was toheoonsidereizl
`mitive-rnat-least-one-ofrhe-tln“eeadjustedlog=ranl.testeoin—
`parisons was less than the prespecified nominal sign'1ficanc.e
`levelfierthateenipafisen.
`[he stratified log—ranK test (stratified on baseline pain and
`
`the primary means ofieteriniriing if FKT q aw anoror PET (1 w
`inc.tea.sedoizerallsu '
`
`
`
`Mhimimrmie r"m1"‘i.1..g;. 11:13 mveka
`Pwdiiisi-ni: 5 rug PITBI11
`IT! cycles
`
`Fry. 1'
`
`"“r.at-inent .:u...l‘l.1fifl.
`
`twice daily for I0 cycles. Prednisone coulffbe continued after
`
`
`I
`
` 5mgwfl3'mi¢$H"fa5wcm.
`
`was also significantly superior for the combined TXT groups
`eernparcdwiEhEhc1\¥I'Zq3wgro&p.Qeerallsui"vi=ealferEl1c
`
`once weelily d00et3X6l aim was not statistically significantly dit3£erent£r9rnthatoftlae1\43lZq3wgrei+p.Pcesultsefthe
`
`comparison ot"TZT q 3w to T q 3w are suminarized"in Table
`%mdmeKap1m—MemwWh$lcw1ebrt
`depiCtedmFig../..
`3‘
`
`|.q.ll|.
`
`H_
`
`P4.'11I—EN—T PQPUL A1‘m m$
`
`The main protocol—speci”fied"inclusion criteria included'lTis—
`
`tate, metastatic disease unresponsive or refractory to hormone
` bymmecmmymdimmdmow
`
`'
`tine rnonotherapy prjor rhenlotherapy was not allowed 'Erear—
`“W. “"‘F“ ”"3P“.“’5P*“"‘.”“"‘ “‘‘’d ‘U ""‘*‘.“‘*‘““.““'W‘ "“f°‘E “‘””'
`domization. Patients with symptomatic peripheral neuropathy
` Criteria
`version 2.0) known brain or leptomeningeal involvement or
`'
`'
`F E9
`255-!
`bene
`.n '
`Em’ fldmhmfif’
`‘ gt
`mmw E” 6‘
`Age, race, Isarnofsky pertormance status at baseline, stag—
`,1 91,24: 3/;
`,1; _:g_!',,Q:-,-,: ,a!9 !,!!,!l
`aerossmefineestudyarinsm 1‘atrle1.theseseerii‘tot:eeverrl5r
`rlisjijhiited arross rreatinenl groups Approximately 84 to 80%
`.
`had
`.
`of pmems Emuflfid F0 each “33u“_Em am?
`3 bagehne ES“
`220. All of the patients had received mior hormonal therapv
`andfor surgery$r halfofa-H
`
`
`
`
`
`"36-
`
`FFFIC my
`lhe primary etticacy endpoint was survival detined as
`
`(«bah 5 mp
`Aae rvemzsi
`M diam
`Paiage
`MS
`QGK I
`Caucasian
`Hagganip
`Lpmai
`uth-I
`MWOYSKY L *3 U70)
`>30
`_7o
`Lhéigv-Ifill
`Stergrrrgat CilclgllL,b''I'S
`
`TI
`III
`V
`Mrsshia
`Gleason am,
`2-4
`5-7
`
`"_[_"5<"T‘ r'i'3‘mr
`W _ «
`3: Karo)
`
`aw
`‘as;
`_ 3341‘: K)
`
`__ _i -2 r'i'3w
`_
`Kw)
`
`sari
`4 — 1.
`8
`312r93.1%i
`9 ,3, 45“
`akogqzro)
`4L'1-
`oi
`
`on
`/A:
`3
`97
`8
`0)
`312r93.4%i
`7 (3, 1%
`2'n.%:J
`JL1-5 0}
`
`sari
`13-86
`F W
`IJI:
`IO)
`312r92.rs%i
`Q 0 W 1"
`9[:n.9.%:J
`DEU-9 0}
`
`293 {B15}
`42 (1? SW
`n
`
`U
`54 (16.1)
`6DI’l§’9W
`19') rs? an
`24* r87;
`
`19 (5,7)
`123 (363)
`
`292 (37.4)
`41 rigs»
`_ Ihla}
`‘
`run)
`49 I‘14.7)
`48I‘_l——4W
`1::
`[57 so
`so .‘_1:..o,
`
`13 (3.9)
`121(36.;2)
`
`2.90 (86.11
`47 Q3 an
`n
`
`1 [U.:))
`56 (16.6)
`5
`(1511
`99 (<4 an
`L6 i13.s;.
`
`23 (6.8)
`19 ('35,?)
`
`te—the elate—ef death Era-in any
`the primary analysis was done on the intent—to—treat population,
`.
`.
`.
`.
` . The study eutofif
` analy sis was March 24, 4003, fl1e‘dam on
`wl1_ir‘.h the sponsor reoeived notification ofthe iafith event 13;?
`tliatdate,a-totalof-55?!eventshad-oectn'red.érfloiLfl1esubjects
`known to be alive at the cutoff date were censored either on the
`
`93‘
`5‘
`103C313 9‘
`10‘ (31-37
`3-.1-“_
`M 5} M 2‘
`93 '-/39-"?!
`38 K’)
`'2.’
`‘ }'*'f'S‘“3HA gm ‘
`J <1.‘:..lIIl FD U1
`ll)
`409
`4m
`537
`Mean
`23
`103
`114
`Median
`rm L209?
`0 16709
`rm 15.40740
`Range
`Abbreviations: PS, performance statm; PEA, prostate ssrze cific an-
`tioeri.
`
`Copyright © 2004 American Association for Cancer Research
`
`C
`
`

`
`UO‘|:TU.‘l'T58TTU7B-U?F32.CCR-U4-1402
`
`Lillllbai K..':lI1f ,1’
`
`i-tc.:<:arci181Z19
`
`Table 2 Overall survival comparison of TX1‘ o3w to MTZ q3w
`TAT q3W
`MIZ Q3“,
`335
`33]
`lberfi 4,‘
`18.9
`16.1)
`Median S1JI'V'1V'Eil(1’fiOI1l.'hS)
`r1r.o_2.1.2.i
`{14.4—18.6l
`95% Confidence interval
` ~ I"IZ6;L
`NLA
`gwflnfiiggqnggepxai
`{rj_1Qf‘I_0" }
`TVA
`1' *
`U.UU)'*|-
`‘T’ Qtratifi ll g-i:ar~l<' *
`"E. To ml“ 11 f '" stat‘'"H al "i-golf‘ an
`d.G1?'5 because of 3 r.d“l‘fi'S.
`
`—
`
`presented in Table 3. Although allergic reactions (all grade) did
`occur , grade. 3—er 4 events
`I
`V»
`t
`t
`t .
`wereo serve
`-III
`00 pa iens
`‘
`Y
`‘1e‘HH8"Pem3 ‘'35 me‘ me“ Eemmefllf’ etsei ed glade g‘ I
`cytopenla, occurrmg in 32% of patients In the T31 q 3W arm
`and22.%intheflmn.Per_iphera1edemaanvdweight<zain
`
`._._ ._..'..._.. -I‘.__..._,_._.. _“._'_.‘._
`El
`.1
`p
`p
`.
`p
`p
`p
`p
`. 0 in ___,1% of
`mums‘ 361-555 the [-11:36 mfitmem 31-“-I5_ AH gmda Card-1 iefi
`ventricular
` V' on the
`MTZq3'w ariri-compared »rs+itl°i'I'XTq3’w 22.}%rcmer-9:6%),
`
`
`
`
`
` 3' ii‘ i 3' Vi
`infusion was equally dislr—b—filiu across Ttfteaens: 3.3% [or
`“W ‘I’:
`3
`'5 ""3 '~ 5
`'[Xj[‘_q 1 2% fgr jjxj‘ q wrand 17% fat M12 q 33;: M95;
`claim for the following reasons: (.11) there was no prespecified
` fim%@k—R3'mfi%&%dwwmo' wm aiemmmm catrsesfirftlre
`endpoints" (£9) only a portion ot patients enrolled were evaluable
`,
`'
`'
`'
`'
`'
` ; and ( )—lar—g., preps-r-
`tions of patients were censored in the analyses for time—to—
`
`
`
`DRUG-DRUG ' TIGNS
`
`Iland
`Eer:ausep£ednisoueisaknonminducerofC‘LE:A."
`3735-(-11), the-two enzyrrres irrvolvedi
`SA-FETY
`(12) the sponsor investigated any potential effect on docetaxel
`Docetaxel dose intensity was slightly lower hi the weekly
` mgmmfl (96“’a—efplan1aedrelativcdesvcifitensity, ck&w&b?ficmiwmwhwm$
`range 62 to I13%i versus the every 5 week regimen (93% ot
`combination. The pharinacofiinetics ot docetaxel were assessed
` *we dose intensi-ty, range 5-1 to LQ'“?7e9.
`differences are not likely to explain the difference found in
`emmqmmome
`iMfl1UHgh39€"'i:Ufp:ItieIItSeIIIUfl“EIlUnTAX327hH[lHL
` mmgemmvamevmLmfimm fionswetenleasiiredwithavajidatedliqiijdchromatographyf
`I“,. I'£II'
`‘I II
`‘
`I "II iv‘III'II
`I.
`,
`.
`'
`5.
`.60 I.l I‘I..
`
`tients. Individual serious or life—threatening adverse events in—
`were analvzgi with the previously developed population phar-
`eluded iirfeetriei-1, anenria, 1-5;.Nos'ig—
`vomiting diarrhea and cardiac left ventricular dysfiinction.
`nificant differences were observed between mean do-cetaxel
`.
`4
`.
`.
`"‘linic.allyi=elevantallgradenndgrade”
`. . .
`-.. _
`
`
`adverse event observed m the IE |q3w and IVITZ arms are
`or with prednisone (day 22) with either docetaxel-doselschedule.
`
`eiirolled to IE I q 3w and 13 enrolled to TELT q w had’5lo-od
`samples collected for docetaxel
`
`-one
`
`"’~—.."'j-i.,
`
`I
`
`K—1‘x?il
`big. 3 uveraii survival
`curve '1"1{Tq3w versus MTZ.
`
`
`
`
`
`'31.FEVIVRKPROiABi,.l.TY O ‘L?
`
`n
`
`n
`
`3
`
`6
`
`9
`
`21
`13
`‘E5
`12
`eu nvixmt. TIME‘ ij‘Moi«.m—is'_i
`
`24
`
`27
`
`an
`
`33
`
`on October 25, 26‘|“1
`Copyright © 2004 American Association for Cancer Research
`
`cabR°'99925 '5
`
`

`
`UO1ITU.‘1‘ 58?‘ U78—0?I32.CCR—0?1—14D‘2
`
`31‘5fl iaxotere for f"LZtreamen c~f‘Prosr.-ate Cancer
`
`Table 3 Clinicallv important treatment emergent adverse events
`
`Taxotere 75 mg/m every
`3xw'e¢s+ 5mg
`'n=33'7(‘.”e)
`
`Mitoxantrone 12 mg/m everv
`3weel.<:s+pn:dni.sLme5mg
`t—w:icedai—15'n=33>5—(‘.”e)
`
` G %
`Anemia
`66 5
`4.9
`r‘ 3'
`
`403
`320
`
` mpmfi
`3.4
`9:15
` 2.7
`1"»/351
`lniection
`32.2
`5.7
`Epistaxis
`5.7
`0.3
` ' 1§ar.u.uns'
`8.4
`Ofi
`Flu-id Eeteatie-H *
`”4—.4
`0:é
`1We1'g1n gain 1‘
`.-.5
`0.3
`Peupheral edema *
`f8.1
`073
`Neuropathy sensory
`30.4
`1.8
`Neumpathv mamr
`72
`L5
` 670
`0.3
`Prlopeeia
`6-5.1
`N1‘-A
`hail changes
`295
`(T0
`Nausea
`41.0
`2-."-'
`Diarrhea
`31.6
`2 1
`StQ;;1;a1j1;ig£pha1;:;ngtjg
`]_CLfi
`(1 Q
` L
`1-8/I
`{+0
`Vfirtntirrg
`1'63
`1.5
`Anorexla
`10.0
`1.2
`Cough
`12.3
`0.0
`Thrsgnea
`L5_l
`2.7
`Ca£diac1efi‘entée«u1a:§uaeEien
`976
`0.3
`Fatigue
`5-3.3
`475
`Myalgla
`14.5
`0.3
`Tearing
`9.9
`0.6
`Arthralgia
`8 1
`Q33
`Abbrevxatlonsz G, grade; N.-‘A, not apphcable.
`* Related to treatment.
`
`57 8
`43.2
`7.8
`1.8
`20.3
`1.8
`Oi
`4.5
`370
`1.5
`7.2
`3.0
`3.3
`1".8
`/.5
`E
`9.6
`8 4
`6:6
`l'4‘.0
`171.3
`7.8
`8.7
`””.1
`34.u
`IZTS
`1.3
`5 1
`
`G %
`LB
`21.:
`1.2
`N/A
`472
`0.0
`0.0
`0.3
`0.0
`070
`0.3
`0.0
`076
`N1‘-A
`GT0
`1.5
`1.2
`(1 I1
`0:0
`1.5
`073
`0.0
`0 Q
`1.”
`5.1
`0.9
`0.0
`L2
`
` mfi<
`recewmg FX1 q 5W than those receivmg X q W, the smafl
`docetaxel plus estrarnustine to mitoxantrone plus prednisone
`sample size ef patients with pharinaeeldaeti-“s—eval+Lah'en dees
`cendectedby$e
`also seem LO show a survival beneht tor a doceLaXel—based
`not allow correlation of peak docetaxel concemrations with
`m
`
`
`
`DLSCUSSLON
`
`Although several single agent and combination regimens have
`
`ugaung the use or docetaxel 1n a less advanced and‘1ess heavily
`retractory prostate cancer and nntoxantrone/predmsone had shown
`pretreatedpopulationofprostatecaneerpauienw Theseresults
`a palliathre e£fe"*, none hawe shown '4 suwival benefit in this
`alsowairantadditionaiinvestigafionofnovelagentsinpafierrts
`semng. The results of 1 !(X32 1 show a survrvafhenefit of dooetaxel
`wflhhcnnnne-refrauoxyprostatecancerwhohaveadsaauced
`given’ wiLha;ue:¢e;§.,r3weel;s’schedulepluspredLusone' inthis
`wrung
`m%mmdwmmogmma
`The shnwn_s_urvival advantage was noredjor the :13 week
`the-rap-3L
`scheduiea11dw‘asnotobservedWiththew‘eeidj1—doeetaxe1
`schedule. As discussed above the small difference in relative
`
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`Copyright © 2004 American Assoclafionufor Cancer Research
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`UO1ITO.‘1‘ 58?‘ U78—0?I32.CCR—0?1—14D‘2
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`f9'9'9;Z'6(:>
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`25’ zfifl C
`Copyright © 2004 Amerlcari Assocrafiorrfor Cancer Research