insertJon in 5’-flanking region of ape AI, 813o CIII, ~po AIV and hence some
`weak changes in appropriate metsbctlc processes.
`
`NOVEL THERAPEUTICS AND PHARMACOLOGY
`
`results
`[~’~’] Clinical and pharrnacoklnetlc (PK)
`studies of the second generation rnatrlx
`metalloprotease (MMP) inhibitor bay 12-9566, a
`non-pepttdlc btphenyt Inhlb|tor of MMPs 2, 3 & 9
`
`of 4 phase I
`
`L. Seym0ur1, L. Grochow~, G. Eckhardt3, C. Edi~hrTmn4, H. H~tte1, R. Goal1,
`R. Humphrey~, I. Eliass, ~NCI-Cana~a C#nlca/TdaJs Group; 2~:~hns Hop/ons,
`Baltimore; ~CRTC, San Antonio; ~ Mayo Clinic, Rochester; ~Bayer
`Corporation, West Havan, CANADA
`
`Introduction: MMPs are invo&,ed in invaSion, metastasis and ang~ogenesls;
`MMPs 2 & 9 are overexpressed in the tumor/stratus of moltipia cancers and
`correlate with outcome in many. MMPs are thus attractive targets for inhibition.
`BAY 12-9,566 has nanom~ar inhibitory actk’lty against MMP 2, 3 & 9 with
`antiqnvaelve, anti-metasta~ and antl-angK)genlc effects in predimcoJ models.
`Method~: 4 dose ranging trials of oral BAY-12~ were conduced In
`North Amedca to define PK/asfely. Dose Ilmibng toxicity (DLT) w~8 tox~.lty >_
`grade (gr) 3; symptomatdc or DL gr 2; MTD was de{~arad ff > 2 patients (pts)
`expedan<:ed DLT, Eligible pts had PS 0-2 and ac~eptal~e organ function.
`Results: 90 pts (median age 67yrs) wtth colon (31), breast (10), renal(t0),
`ovary (8), sarcoma (7), melenoena (6) and other cancers (18) entered 9
`dose levels. Dose related effects were limited to redL~-’tion in Natstat c,O~Jnts
`(pi~s)(nedlr d 15-27) raver*Jble with continued therapy; in 4 beavtty pretreated
`pt8 pits fell to gr 2/3 leading to prophylactic do~e reduction; and mild anemia.
`Mild reversible transamlnase elevations and GI afro.s (nausea, flatulence)
`were observed in soma pts; musouloske4etal effects were not reported MTD
`was not reached although DLT (pits) was seen in 1 pt at DL 6, 8 & 9.6 pts
`remain on study (mean 236(I [140-314d]). 1 pt with refractory melanoma (3
`prior regimens) had PR < 4 wks duration; 1 pt with refractory ovadan cancer
`(7 pdor regimens) has SD after 9.5 months.
`
`Dose Level (DL)
`
`1
`
`2 3 4
`
`Number of p~ (N)
`
`Total/d~ay(m,g)
`
`Dose(rn,g)
`S~:tle~u ~
`D28 Trc.ug h (rr~,&n; m94.)
`
`10
`
`3 3 3
`
`100 125 150 200
`400
`100 125 150 200
`OD OD O~ OD OD
`64
`37 51
`72
`38
`
`400
`
`5
`
`18
`
`8
`
`10
`
`800
`
`4or)
`BID
`125
`
`7 8 9
`
`15 12 18
`
`1200 16~0 1600
`
`400
`480
`TIE) QID
`125
`117
`
`BeD
`BID
`13~
`
`Molecular oncology / Novel therapeutics and pharmacology
`
`Foud~ f~ur pts ere evaluable for re._~oonsa and 3 pts are too early: 9 partial
`responses (7 mesothelloma, 1 pancrea~ cancer, 1 renal carcinoma) 18 stalYe
`disease and 17 pro~lressive disease.
`Conclusion: Thin combination ~s well tolerated and has shown actMty. In
`the light of these good resulls, we are planning two phase II tdals at a dose of
`3 mg T and 130 rng of L~HP: one In mesothelloma and another In advanoed
`co~rsoEd cancer.
`
`[~-0~-] Phase I study of RPR109881A, a new tsxold
`administered as a three hour Intravenous Infusion to
`patients (pts) with advanced solid tumors
`
`(~. Sesse’~, S. Celd~era’t, J. De Jo~gI, C. IVk)nnera~, D. P~rard3, L VemllleP,
`A. Rive3, M. E~enval3, J. B~ue~. ~O~p. San G~,~nni, Bellirlz~na, ZCHUV,
`lausanne, Sw#zerland; a Rh~ne-Pou~-~ Rarer, Antor~, France
`
`RPR109881A has shown a broad spe~rum of activity in In viva and in vftre
`tumor rnode4s and Is able to cross the bkx~ b~n harder. Five phase I
`studies are ongo=ng to define the recommended dose and schedule (1o, 3-, 6-,
`24-hour and 1 -I-,3~Jr dl-d8 q3w). We re$)ort the preliminary results of the
`schedule with an oral premedicatlon with dexamelhasone (-25, -13, 1-hour).
`The starting dose of 75 rng/n~, was defined according to the safety profile el
`pts treated with other sohedulas (1-ho~r/6-hour}. Dose escalabon was done
`according to the modified Flbonacd’s 8dnedule. 13 pts (9 males/4 females -
`median age: 52) prevtous~ treated with _< 2 prior ct~,’notheraples (CT) ware
`inc~uded. The dose lirr~ting toxic~es (DLTs) are as follows:
`
`50% pts presented neutro~enla Gr.4. AIo~e~la Gr.2/3 was universal; other
`toxictties were: arthralgm, nausea, rash of mild to moderate severity. O~e pt
`d=ed because of viral Infection while neutn:~enlc after the 4th cycle. Blood
`samples were collected ever a 0-48 h parted for PK analysis. PK parameters
`were similar ever the 2 teste~ ~ ~ mean values at p~srna c~earance.
`volume of dlstrlbiJbon and terminal haft-life of ~ 40 I../~m~, 10~0 L/rn~ and 3~
`h, resp~Etively (n=11). Additional pts will be t~eated at 90 rng/m~ (_< 1 prevl~JS
`CT) or 75 reg/n~ (< 1 previous CT + RT) and randomized between 1-h versus
`3-h to establish the best .schedule and to confirm its feasJbility for phase II
`study. Two confirmed partial response In 2 NSCLC pts has been observed
`at 90 mg/rnZ: one untreated pt presented brain metastases and responded In
`both lung and brain lesions.
`
`~-~ Evidence for the durst|on of the antifolate action of the
`thymldylate synthase (’rs) Inhibitor ZD9331 using
`plasma dUrd aa a surrogate marker of enzyme
`inhibition
`
`A. L Jackman E Mitchell, S. Lynn, G W. Aheme, C. Re&s, A.H. Calvert,
`I.R. Judson, S. Dtab, K. Mayne, M. Smith. thaZD933t Phase Ilntemationa]
`Invest~ators Group; CRC Centre for ~ The~, The Institute of
`Cancer Resesrc~h, Sutton, UK
`
`Introduction: Inhlb~bon of TS by ralbtrexed (To.mudex~; Zeneas) or the non.
`p~yglutamatab~e drug ZD9331 leads to a dee m th~ level of Intmcellular
`dUMP and henc~e p~esma dUrd In mica end humans. Pla.sma dUrd levels ware
`measured in four phase I dose escalating trials of ZD9331, Including t~ thals
`where a 30 mm =nfusJon was gwen either on day 1 or on days 1 and 8, v4th
`cymes repeated every 3 weeks.
`Method~: Pre- and post-treatment blood s~rnp~es were Immediately coo~ed
`on ice end spun to separate the plasma (stored at -70°C), Fotiowtng de-
`protelnlsetlon and ~id-phaas extractlon, samples were anelyr:,ed tar dUrd by
`isocrat~c reverse-phase HPLC using a spectral scanning UV detac~or,
`Results: B~th trials started at a dose of 4.Srng/m2/d. A dee (~2-fold) in dUral
`was seen at th~s dose that was of ~48h durati~’~ (-.,d2-3/dO~10). AS doses
`increased, a more prolonged effect and in s~ne patients a greater rLse In dUrd
`levels was seen e.g. at 19.2n~/m~/d, 3 patients had 3-4-fo~d rises on d2 that
`had not returned to pre-treatment levels by dS. In those patients who had e
`second dose on d8, a further rise in dUrd of the same magnitude occurred on
`d9 w~th return to pre-treatment levela by d15-22. At 32mg/rn~/d, some patients
`had plasma dUrd that had not completely retumed to pre-treatmant leve~s by
`de. O~e patient had 5, 2, ~ and 3-fo~d rises on days 2, 8, 9 and 15 raspacttvaly.
`These data pro~de evide~::e of TS ~nhJbition that is of longer duration with
`increealng doses of ZD9331. Two patients at 4.8 and 9.6m~rr~td on the dl
`and 8 schedule showed a parcel and minor tumour re.~x}nee respa~;tively. The
`trials are ongoln9 and the MTD has not yet been reached.
`
`AUOo.,.24D28(meBll, rn~) 1161
`
`-
`
`1739 1411 2300 3035 2275 3135
`
`Conclusions: Oral BAY 12-9566 (800 mg bid) is well tolerated wtth trarks~nt
`and usually cfinica!ly insignificant decreases In pit counts and mtid anemia the
`only dose related toxidtJes.
`
`Tomudex~
`~-~-] Updated results of a phase I trial of
`(T) In
`combination with oxallplatln (L-OHP) in advanced
`~olld tumors: A promising and active combination
`
`M. Ducreux, K. FIzaz], C. Daniel, P. Ruffid, A. Kabob:be, A. Fandi, M. Smith,
`J.P. Arm,and. Instltut Gustave Rous.s24, Vil,~juff (France), Zeneca
`Pharmaceuticals, Cergy, (France)
`
`Introduction: The aim of the study is to determine the me.mum tolerated
`dose and the recommended dose for subsequent phase II trials. The dnferent
`mechanisms of action and toxic~! profiles of T and L-OHP are the rationale to
`test their combination
`Methods: T was administered as a 15 minutes infLmlon toJlowed by L-OHP
`a.9 a 2 hours Infusion, repeated 3 we~kly. Dose escalation Is shown below:
`
`~ le~e~
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6 7
`
`T/1.-OHP
`
`2,185
`
`2.,~
`
`2 5,/110
`
`3/110
`
`3/130
`
`3,5/130
`
`3,75/130
`
`Number of
`
`3/10
`
`3/21
`
`3/12
`
`3~10
`
`16/63
`
`14#61
`
`Patients:. so far, 47 patient8 (pts) have been entered: 30 M/17 F, median
`age 57 yearn (29 - 72), PS (WHO)’ 0 = 15, 1 = 25, 2 = 7. Prlmary neoplasms
`were malignant mesothelion’m (17), gastr~ntastinal mallgnandes (14), renal
`cardnoras (5), lung c;~u’~er (4), other (7). Thlrl~ six pts were pre-treated.
`Results: During tbe first 4 levels, no Oose-Ilmiting tox~ctty was Oaserved.
`An esymptorsettc Increase in trans~nlnases was frequent whatever the step.
`Dudng the subsequent steps, grade 3 + 4 toxk:lties Ir~--duded: pts (cycles)
`Step 5: vomiting 3 (3), diardx~a 2 (3), neutropanla 1 (2), thrombocy, topenla
`1 (1), anemia 2 (2), peripheral neutox]c~ty 1 (1), setben=a 1 (1)
`Step 6: vomiting 2 (2), neurotoxlc~ (fugax amauresis) 2 (2), astherda 3 (4),
`anemia 1 (1), thrombocyto,penla 1 (1), diarrhoea 1 (1)
`Step 7: is ong~ng and no grade 3-4 toxlcffy was observed. However,
`gestro~nte~nal toxk~ties and es~henia seem doae-llmi~ng.
`
`A~mals ofOncology, Supplcmcnt 4 to Volume 9, 1998 ~ 1998 Kluwcr Academic Publisl~rs, Printed in TI~ Netherlands
`
`125
`
`Sandoz Inc.
`Exhibit 1043-0001
`
`Teva – Fresenius
`Exhibit 1043-00001
`
`

`
`Novel therapeutics and pharmacology
`
`Conclusions: A rapid, cer~tive and reliable method has been dave4opad for
`the measurement of plasma dUrd in patients receiving anbk~ata drugs. These
`data suggest that the duration of TS Inhiblt~on is do,se-r~ated and w~ll help In the
`chics of dose end schedule for Phase II trla~s of ZD9331 and understanding
`the relationship of dural]on of target =nh~b~tlon and response/toxicity.
`
`r~-~)--5-~--] Strategies for Improvement in dose escalation using
`the continual reasseaament method (CRM) In phase I
`clinical trials
`
`LL Siu, X. Paolaftl, J. O’Oulgley, E.K. Rowinsky, G.M Clark, D.D Von Heft,
`S.G. E~hardl. Cancer Therapy and Research Canter, San Antoni~ TX, USA
`and U436 INSERM, Paris, France
`
`The CRM t’~as ~ pro~3~ as an alternative dose asealat~on method in
`the pt~Lse I clinical tdal deign of antineopfastlc agents, with the aim of
`exlx~r~g a greater pro~orl]on of patients (pts) to therapeutic drug doses than
`tradi~onal approaches. "]-he sta~t~al model utilized is a sequential Bayesian
`estimation scheme in which a pdor distribution function of the rea~mum
`toterated dose (MTD) and a dose toxic-response model are selected before
`the tdal, The MTD Is the dose at which a predetermined percentage (e.g.
`30%) of tl~ pt population would expedenea dos~-Ilmitlng taxicily (DLT, e.g. Gr
`3 no~’~-hematolog~c o.r Gr 4 harnalolog~c). In respanse to the pract~.~l and eafery
`concerns of cytotoxic ct’~rr~therapy, rr~d~tlons of the CRM (MCRM) were
`Implemented which Include the use of a c,o,nven~lonel ~lartlng dose and the
`fixation of dose levels a pnon, ¢ustomanty by al:~y~ng t~e modified Fiboeac~l
`sequence. However, our experience with th~s dose escafal]on method has
`been problematic due to the dependence on non-d~rdeal toxic~ity inforrnation
`pdor to the trial, and the diff~J~f of pred~cllng a fixed number of dose levels.
`Therefore, we have designed a "dual-stage" escalation scheme. The ~nitial
`stage involves utilization of a conventioeal starting dose with doub~ing of the
`~ in s~ngle-pt coharts until moderate toxicity (e.g. Gr 2 non-hematologic or
`Gr 3 hematologic) IS encountered, at which point 2 addit~oeal pts ere ac~red
`and do~e esca~tion proceeds in a more conservatwe manner (e.g. at 33%
`to 50% Increments). ~ne s~ond stage begins once DLT Is reached, and the
`CRM is used to guide subsequent assignment of dose levels Instead of the
`Bayesian mathadofogy, a maximum likel~hoed ap~reach (O’Qulgley and Shah)
`Is at:~lled which offers greater f]exibll~ without restriction by the ppaL~Ctty of
`prior data. Pracl]cal examples and s~mulal]ons of models will be pn:wided to
`illustrate this pro~ dose escalation method.
`
`I~ Synergistic antltumor effect by novel modified
`ollgonucleotldee targeting PKAI combined with
`cytotoxlc drugs or monoclonal antibodies
`
`G, Todora, V. Damiano, R. Blanco, S. Peps, A.R. Bmr~co, S. Agrswal1,
`J. Mendelsdnr~, F. Clardiello. Onc~ Medics, Univ Federico II, N~I,
`Italy; 1Hybfidon, Cambridge, MA, USA; 2UT-MD Anderso~ Cancer Canter,
`Houston, TX, USA
`
`Introduction: Prote~n kinaea A type I (PKAI) plays a key rele in neoplast~
`transformation ~ conveys mltogenic s~gnals of different growth factors and
`ano:)genes. Moreover, PKAI ~s overexpras~ed =n cancer calls with an acl~lve
`TGF~-ep~derreal growth factor receptor (EGFR) eut~cdne pathway and ,~ows
`a structural and function,~l interaction wttl] EGFR. Inhib~on of PKAI, or its
`regulatory subunlt R~,, results in cancer growth =nhlb~tion in vitro and in viva.
`Methods: A novel ctass of mixed backbone oligonu~leotldas (MBOs) tar-
`gating PKAI (ASRla), wffh Improved pharmaceldnefic and btoavallab=hty, and a
`humanized rnenecJonal antll:x:x~y which blocks actJval]on of EGFR, MAb C225,
`have been tasted In vitro arid in vivo on several human cancer cells.
`Results; A dose-dependant inhibition of soft agar grow’~ was obtained in
`all cancer types tested w~th the AS RI~ MBOs, as compared to mismatched
`contro~ o~lgos. Non-Inhibitory doses of each MBO resulted In a synergislJc
`growth inhibition and increased apoptoals, when combined with ta~anes,
`p4atinum-derivat~vas and tope II-setectlve drugs. W’ne~ the MBOs admlnlstarsd
`either i.p. or p.o. were added to pad~taxel, a cooperath, e eftect was also
`obtained in vtvo, causing tumor growth Inhlbit~n and increase of survival in
`nude rr~ce beadng human cancer xenografts Finally, comb~ead treatment of
`human breast and renal cancer ce~ls, whK;h overexpress PKAI and EGFR,
`wi~ the ASRla, MBO and MAb C225, CaUSed a co~nerelh, e antJtumor effect in
`vitro and in vivo.
`Conclusions: Since both the AS R~ MBOs and the MAb C225 are currant~
`studied In ctlnice~ trkds, the combieation between them or with selected
`cytotoxic drugs may represent a feasible novel therapeutic strategy
`
`~ Pharmacoldnetic (PK) Interaction of the combination
`of doxorublcln (DOX) and Taxotere (’TXT)
`
`J. Sch011e[, M. Czejka, E. Krex~er, K. Lehner, H. Bucher, G. Schemthaner.
`Hospital Rudo#st~fiung OflcoL Dep., Instlt phanna chem Vtanne, Austria
`
`Introduction: Cornbleat~on of DOX with TXT has been shown to be highly
`effe(~tlve in advanced breast cancer recently Intr~dL~d into edluvant treatrnent~
`Purpose of th~ present study was to detect a potent~l PK intsractles between
`
`DOX and rXT, as already proven for Paditaxel + DOX leading to increased
`DOX-AUC and enhanced car~iotoxiclty (Glanni et el). Therefore PK behavior
`of beth, DOX and TXT, was ansly’zed using 2 different time schedules: DOX
`50mg/rr~ 30rain inf. followed immediately (A) of after 1HR interval (B) by TXT
`75~ng/m2 1HR Infusion.
`Methods: All pts re(:elved TXT atone at cycle 1 for baseline determination
`followed by D, OX + TXT (18 pts ~ule A, 13 pts B, s~mp,ling for both
`and TXT), followed by DOX baseline analysis (12 pts A, 6 pts B, TXT then
`given delayed after end of DOX sampling). Sampling padod 4HR for TXT and
`6HR for DOX, measured by HPLC, Win Nonlin r~ncompartimental analysis
`performed.
`Results: of the respectwe AUC last:
`
`AUC
`
`ng/ml’H
`
`A
`B
`
`Taxotere
`
`n
`
`18
`13
`
`TXT
`
`14~4
`1703
`
`DO)~TXT
`
`1956
`2450
`
`p
`0.03
`0.05
`
`n
`
`12
`6
`
`Doxoruld, cln
`
`COX
`
`DOX/TXT
`
`859
`906
`
`848
`8.33
`
`p
`0g
`0.6
`
`Conclusion: No Influence of TXT on DOX-AUC documented, DOX-ol conc
`(n=8) w~th or ~ Tx-r n.s. different (p 0 2 - 0.8), thus expl~uning low
`eardioto;,ddty of the co.mblcaflon. In c,ontrast, TXT-AUC was s~gnlflcantiy in-
`creased when co~nblned wflh DOX, suggesbng interference at the hepatic
`rr~rosomal level, partly ex~aming high ¢~inlea~ effica~. A 1HR delay between
`end ~f DOX and start of TXT does not change the respe~ve PK behavlour of
`both drugs.
`
`~ Gemcltablne (GEM) - clsplatin (CDDP): A schedule
`finding phase 1/11 study
`
`J.R. Kroep~, G.J. Petars~, C.J.A. Van Moora~~, J.B. VerwIorken3,
`P.E Postmu~-, A. Catik~, H.M. Plnedo~, C.J. Van Gro,m~inges~. ~Dept. Or~.
`and 2Pulm., Univ. Heap. VU, Amsterdam, NL and 3Dept. OnooL, Univ Hosp.
`Anh~veqo, B, TI~ Nethedands
`
`Introduction: Gem and CDDP are a~ve against vadous solid tumors. S~nce
`preshnleal studie~ demonstrated the efficacy of various ~edules we evaluated
`~ tolera~Idy and c~lnleal efficacy of 4 different Gem/CDDP schedules as part
`of a pharmacekine~ and -dynamic (PWPD) study.
`Methods: Gem 800 ru~m2 ~ administered as a 30 rain infusion on d 1,8,
`15, and CDDP 50 m0/r~ over 1 hr on d 1, 8 every 28 days; Gem 4 hr before
`CDDP (10 pts), or vice versa (14) end Gem 24 hr before CDDP (9), or vice vers~
`(9), after one c’f~a followed by the revars~:l .s~-tedule. Pts (19 male/’23 female.
`median age 54 years [31-77J, and p~rformance status 1 [0~2]) included,
`ovarian, 7 non-small c~l lung (NSCLC), 5 head/nec~ squarnous cell (HNSCC),
`5 esophageal, 4 melanoma, 4 cervix, 3 edanoearcth<~ma, 2 pancreatic, 2 colon
`and 1 small cell lung (SCLC). 26 pts rec~ved prior c~emotherapy, of which 21
`p~atinum based.
`Results: A mean of 4.2, 2.6, 3.8 and 3.5 ~ was given in the four
`schedules, reap. The most frequent overall grade 3,/4 CTC-toxic~ty was thro.m-
`bocytopenla, 6/10, 4#14, 2./9 and 6/9 (overall 6~%), foitowed by leukopanla,
`6/10, 5/14, 6,/9 and ~ (43%), in the 4 schedules, rasp. Therefore, Gem was
`not given ~n d 15 in 36% of pts in cycle 1. Anemia was observed in 64%
`of pts. No sedeus bleeding oc~urrad. Mye~otoxk~ity was cumulal]ve, b~t not
`s~hadule depandenL Non-hematolog~(3al toxl~t~ consisted rn, alnly of grade
`eausea/vom~r~g and tat~gue. O~e pal]ant died of toxic~ following severe nau-
`tropen~a and seps~s. Creatinlne c~earance decreased s~ghtiy dudng therapy.
`AntHumor effects In 36 evaluab~e pts: HNSCC, 1 CR; e~:~ohageal, 1 CPJ2PR;
`ovadan, 2 PR; NSCLC, 1 PR; melanc-ma, 1 PR and adeno~arcineme, 1 PR.
`Conclusion: (Cumulative) myek>suppress~on was the mejor toxicity,
`though it was not schedule dependent. Based on toxicity, eff~eacy and PK/PD
`data a p~ase II sb.~dy, CDDP 24 hr before Gem, has been started in pts with
`upper gastr(Hntastinal tumors
`
`I-~-~ MTA (LY231514): Relationship of vitamin metabolite
`profile, drug exposure, end other patient
`characteristics to toxlcl~j
`
`C. Niytk~za, S. Baker, R. Johnson, J. Walling, D. Seilz, R. ~k~n. UI/y Reseamh
`Laborato#es, Indiana, USA; Cancer Treatment and Research Center, Texas,
`
`USA; Unlv of Colorado Hea]t’h S~ences C~ntar, Col~rado, USA
`
`Introdu¢~on: MTA ~s a nove~ muititargeted ant~falate wilt1 Inhlbltocy activtty
`against mu~ple enzymes. Phase [/]1 studies have show~ activity in a vadety
`of turne.rs Historical data on other antifolates have suggasled that a patient’s
`nutn’donal status may pfay a role In the likelihood of expadanctng severe toxic~ty.
`The purpes~ of this study was to assess the retationshtp of vitamin metabel~as,
`drug exposure, and other prespec~fled baseline pa~ont characteristics to toxicity
`follo~ng treatment wrth MTA.
`Methods: Homocystelne (Hcys), cystathlonine and methytmalon~c acid were
`measured In 139 phase II patients wflh tumors of the coton, breast, pano-eas,
`and esophagus at base, ins and once each cy~e thereafter. Stepwtse regres-
`sion modeling, multlvaitate analysis of variance, and discrimthant analysis
`were implemented to determine which predictors might correlate with severe
`toxicity after one corJrSa of MTA. Progn~tic factors consk~ered ware age, gen-
`
`126
`
`Annals of Oncology, Supplement 4 to Volume 9, 1998 ~ 1998 Kluwer Ac~demtc Publishers, Pnnted in Thc Nethcrtands
`
`Sandoz Inc.
`Exhibit 1043-0002
`
`Teva – Fresenius
`Exhibit 1043-00002
`
`

`
`tier, prior treatment, base~lne albumin, liver enzymes, ANC, p~atelals, v~tamln
`motabotites, and AUC.
`Results: Statistically sigruficant predictors of Grade 4 neutropon~a (n=21
`pts) ware albumin (p = 0.0006) and Hcys (p = 0.0012), whde Grade 4
`thrombocytopenia (n=8) was h=ghly predicted by Hcys (p < 0.0001) end
`pre-trestment AST (p = 0.0012). Hcys _> 10~M predicted Grade 4 neutroben~a
`In cycle one 75% of the time. Grade 4 neutropanla was predicted by Hcys
`alone In 70% of ca,sos. Hcys and albumin levels dk:l not apt:~ar to change
`Irom baseline dudng treatment wdh M’rA While AUC was not found to be a
`predictor of toxlclty, little vadab4tiy was observed In AUC. Maximum values
`were still below AUC values related to hematologic tox~c~y in pl-~e I studies
`Conctualona: Toxic~os resu~ng from treatment with MTA appear to de
`predictable from pratreatmont homosystalne levels. Elevated base~ine ho-
`mooystelne levels (>_ 10/~M) highly correlate with severe hematologic and
`nonhemato~ogic toxlclties fo~lowing treatment with Mq’A. Hornocystelne was
`found to be betler than albumin at predi~ng toxicity. These results ap~y to
`the tumor types studied. Fudher studies are underway’ in patients wflh rene/
`impairment or patients who received pd~r clst:dabn.
`
`[-’~’~’~)"P--’I Phase I and pharrnacoklnetlc (PK) study of Tomudex
`(TOM) + 5-Fluorourecll (5-FU) and levofollnlc acid (LFA)
`in advanced head and neck and colorectal cancer
`
`F, OSlX~t~ro, R, Cesaret~, H.L. McLeodt, A. Budillon, G. Cadeni, E De V~ts,
`A, Avallone, M, BIglietto, A. Tucc~, J. Morsmen1, D. Barberulo, G. Cataleno,
`P. Cornelia, G. Cornelia. Southern Italy Cooperative Oncology Group c/o
`National Tumor Institute of Naples, ITALY,. t Unlversily of Aberdeen, UK
`
`Background: Synergism between TOM and 5-FU + LFA is observed In vitro
`w~en cells are exposed for 24 hours to TOM, followed by 5-.FU + LFA.
`Pre~inlcal studies supped the idea that TOM might down-regulata the ac~,~y
`el dihydn3pydmidlne dehydrogesase (DPD).
`Patlo~ts end methods: Patients (pts) with advanced heed and neck and
`colorectal cancer ware treated with escalating doses of TOM on day 1, and
`b~us 5.-FU (Immediately affer LFA) on day 2, every 2 weeks. In the 2’’d co~rse
`LFA and 5-FU were administered on day 1 and TOM on day 2 wilh the aim
`of evaluating DPD and 5-FU AUC w~h and wflhout pratreatment w~th TOM.
`Further treatment was grven aco:~rdlng to the sequence used in the 1= course.
`Results: Avatiab~e d=nlcel data are surnrr~dzed below.
`
`Step
`
`TOM/I.FA/SFU (mg/n~) R~ C/HN" DLT
`
`Type"
`
`Response
`
`1
`
`3
`
`4
`
`5
`
`7
`
`8
`T~tal
`
`1,5~5G/600
`
`2 Q,’25~/750
`
`2 ..~2 501750
`
`2.5/250/900
`
`3 0~50/1050
`3 0~250/!21;O
`
`6
`
`8
`
`6
`
`7
`
`16
`
`3
`58
`
`1/5
`
`0/6
`
`0/6
`
`5/1
`
`5/1
`
`0/1
`
`9/7
`
`2/1
`
`41/17
`
`Q/6
`
`016
`
`0/7
`
`3/15 N4, N4;N4
`2_f3 N4, M3, R3
`
`1/6 (PR)
`
`3f6 (2CR. 1PR)
`0/7
`
`6~13 (1CR, 5PR)
`
`1/3 (PR)
`OR
`
`"C - ¢olore~ c~ncer;, 14N=he.ad & ne¢~ car~sr. C - 5/39 (15%J; HN = 7/16 (44%}; " N -
`ne~tropen&; M - mu.cc~’t~, R - Renal
`
`DPD activity has been measured =n 14 pts thus far. Pratherapy DPD activ~y
`was a median 34% higher than after TOM administration (95% C.I. -93 to
`+62%), PK data are available ~n 6 patients thus far, ~ 5-FU AUC basal
`values do not algnltioantiy differ from vatues obtained 24 houm after TOM.
`Conclusions: The combination of TOM+ 5-FU/LFA is wall toforated ovary
`2 weeks. Clin~_Jal ectivit~ looks very encouraging, since the majortty of pts had
`already reeaWed pdor chemotherapy. We are now treating scene addFeonal
`chemo.-nalvo patients at step 7, in order to have a more raliab/e estimate of
`the activity of the regimen.
`
`~ Radio-localization of pulmonary nodules using
`
`gamma-probe and resection by video-assisted
`thoracic surgery
`
`A. Challa, G.F. Menconi, F.M.G. Me~fl, A. Gonflotti, G. Boni~, G Gro~so~,
`E, Baldinl2, C.A. Angelet~. Sen/ida of Thoracic Surge~ Deparlment of
`Surge~ ~ Service of Nuc~ear Medi~ne and 2 Service of Medical
`Depar’trnent of On~otog~, University of P~sa, Italy
`
`V~deo-assisted thoracic surgery (VATS) is emerging as safe procedure for
`diagne~s end treatment of peripheral bulrnosary nodules. One hmltaflo~ of
`thoracescep~c te~nnl~ue Is the inabilrty to detect those nodules which are very
`deep beneath the pleural surface, and could only be Identified via manual
`palpat~n. Several methods are used to Iooallze VATS o(~ult laslon~ prior to
`excision, including methylene blue InJec’don end intredu~on of hooked-wire;
`however, all suffer from limltatior~s. Recent advenoemants in Intraoperative
`rao~o.-Iocallzation of non-palpable breast laslo,ns prompt us to develo~ a new
`technique for detection of pulrnonary nodules by VATS. CT-asan are used
`to guide bedleslenal injection of 0.2 - 0.5 ml of solution of 99m Tcqabaled
`human serum albumin ml¢~,s.p~neres (5--I 0 MBo~ and 0.2 ml of iodine-non-lame
`contrast medium, two hours before surgery. In VATS a gamma ray detector
`(S~nti Probe MR 100 - Polhl.te~h., Aquila, Italy), equipped with 1from
`
`Novel therapeutics and pharmacology
`
`diameter-eallimated proOe, allowed us to locate that lesion for thomcesce~t~c
`resec~on. From June 1997 to January 1998 we treated 15 conse,~--’utlve patients
`(pts) wibh sub-centimeter pulmonary nodules. Nine pts ware affected by e
`synchronous and metachronous maligr~ant neop~a.sm in other sites. C..43mputed
`thernography of the chest helped in the planning of the operative procedure, the
`bonbon of pts, and ideal ports. A hot-spot was easily detected, in all patients,
`by the probe Introduced in the ptaural soace through e 11.5 rnm tracer. The total
`excision of the lesioa was confirmed by detection of radioactivity in the removed
`sbec~men and its abse~oa in the resection margins of the lung. Pathe~ogical
`examination of specimens ~ 8 benign lesions and 7 maligrmnt le~or~
`(4 matssteaes and 3 lung sanoar) and it confirmed the absence of Infiltration
`In the reae~on margins Tl~e surgical procedure was exteru:led for an average
`of 56.6 minutes (range 35-100 rain). The average post-operative hospital stay
`was 3.6 days (range 3-6 days) In our experience this ter~nique proved safe
`and accurate, allowing easy detection of the pleural surface p~ectten and fast
`removal of the les4on. This technique offers a simple and relkd:~e method for
`Io~.ahzatiea of pnmary and metastatic tumors by VATS.
`
`~"~ Pharmacoklnetlc (PK) of Tomudex~ (raltltrexed) (T)
`and oxallplatln (0) combination: Preliminary results of
`an ongoing phase I study
`
`K. FizazP, M. Bonnayt, D. Fourcaultt, P. Ruffi~~, O. Couturesz, M. Smith2,
`R C-omanlz, A. Fandi2, J.P. Armand~. ~lnstit~ Gustave Roussy, Villejuif,
`2Zeneca Pharmaceuticals, C.erg~;, France
`
`Introduction: The a~m of this stu~ was to evaluate the possible kinetic
`interactions betwoen T and O administered to patients with advanced disease.
`Methods: Patients first received T (15 rain Infusion), fo~lowed 45 mlnules
`later by O (2-h{mr Infusion). Three patients receha~ T at a dose of 3 ms/rr~
`and 3 at a dose of 3.5 mg/m2. All of them received the same dose of 130
`rr~rr# of O.
`P.e~ult~: Piss.me co,ncontrations of T dectined td-ox:l:x:~entially after the
`end of the Infusl~n. The terTnlnal tl/2 dedved from samples up to 28 hours
`post-dose vaded between Individuals from 9 3 to 193.2 h w=th average values
`of 73.4 and 33.7 for the two dose levels. The max=mal conoentratior~ reded
`between 323 and 1185 ns/ml with averages of 6~1 and 813 In the 3 rng/mz and
`3.5 rr~/n~, groups respectively. The AUC reded between 720 and 3192 ng.h/ml
`with average of 1577 and 1378 in the two groups. The comparison between
`the two groups did not revealed any d=fferance, probably due to the very largo
`Intra subject vanabtlity, however the mean AUC showed an appro;dmataly
`proportlooal increase w~h =n~eas~ng dose. The estimated kinetic parameters
`were In agreement with the values previously published. Ptssma concentrations
`of O declined bi-expanentially after the end of the infusion. The terminal tl/2
`varied from 18 to 30 h (average of 25). Cma~ ranged from 3.13 to 4.53 (average
`of 3.69) .~g/ml. The AUC ranged from 74 to 12~ (average of 195) l~g.l’dml end
`the CI vaned between 1.76 and 3.43 (average of 2.47) 1/h. Yha comparison
`of the kinetic parameters of O to the ones previously published in the sarr~
`experimental condrttons seems to indicate that T Induced an inctesse of O Cl
`(from 1.32 to 2.47 1~) with a reduc~on of the terminal tl/’2 from 38,7 to 24,8
`h end a reduction of Cmax measured at the end of the infusion from 5.11 to
`3.69 ,u.g/ml.
`Conclusions: These preliminary results suggest that the expected concen-
`tratJoos of O obtained after administration of T may be lower that the ones
`observed when O is admin=stered alone. These results Indicate possible PK
`Intarecbon between the ~ drugs,
`
`~-~A phase I and pharmacoklnetlc (PK) study of ET-743, a
`novel minor groove binder of marina origin
`administered on a dally x 5 schedule
`
`M. H~olgo, M.A. VIItalone-Calero, S.G. Eckhardt, G. Weiss, E. Campbell,
`M. Kraynek, J. BeiJnan, J. J~meno, D. Van Hoff, E. Rowthsky. Canoer Therapy
`and Research Center, San Antonio, TX, The Netherlands Cancer Institute,
`Amsterdam, The Netherlands; PhannaMar, S.A., Madnd, Spain
`
`ET-74-3 is a novel totrahydro~soqulno~ine alkaloid isolated from the matins
`organism Estena~sck~n turb/nata which b~nds to adenine-cytosine rich rag~
`within the minor gro~ve of DNA. This study is evaluating the feasibility end
`PK behavior of ET-743 admin=stered as a 1-hoar infusk)n dally x 5 every 3
`weeks in patients with adverted solid malignancies. Twenty-seven patients
`(median age 58, ranoe 35-79; rr~dian ECOG PS-1 ) have racelved 67 courses
`of ET-743 et ~ ranging from 6 to 380 #g/rr~./day. At the 380 #g/rn=day
`dose leve~, 1 patient with extensive pdor treatment with 16 c~des of BCNU
`developed grade 4 thromlx~’ytopenia, grade 4 neutropanla wtth fever, grade
`3 elevation in transemlnasas, and acute rer~al fadure which resulted in death.
`Four patients (8 cycles), at the 216 (1), 287 (1) and 380 (2) #g~T~21day dose
`level developed asyrnptomatic elevation m hepatic ~lnasas of grade
`3 severity that t~picetiy peaked on day 8 ar~ ras~ved by day, 21. Mdd to
`moderate, deaedependent eau~ea and vomiting, whkih appeared on day 4
`and resolved o.n day 8, was observed In 14 patients. Two patients at the 380
`#g/n~-/dey dose level suffered superf~al venous thrornbephlebttis at the drag
`Infusion site. PK parameters obtained in 2 patients at the 216/~g/rr~day ~
`level ~r~luded: dearan, ce, 137 and 589 m L/mtiYn~; hf~, t 3.7 and 23,1 L/h; and,
`
`Annals of Oncology, Supplement 4 to Volume 9, 1998 ~) 1998 Kluwer Acadcrmc Publishers, Printed ,n The Neth, edands
`
`12’7
`
`Sandoz Inc.
`Exhibit 1043-0003
`
`Teva – Fresenius
`Exhibit 1043-00003
`
`

`
`Novel therapeutics and pharmacology
`
`AUCo-~h, 158 and 587 ng-min/mL. AUC.,~ (790 and 1835) were >_ than
`the mouse AUC at the LD10 (854 ng-mln/mL). No drug accomulahon was noted
`from day 1 to 5. In condus~ee, ET-743 produced severe tox~y wflh murdorgan
`Invotvarnent at the 380 /.tg/n’~-/day in one exceptlona/ly heevfly-pretmated
`patient. Additional sub, eats are being evaluated at this dose level to define the
`M’I’D of ET-743 on this schedule of administration.
`
`J~"] A phase I and pharmacologic study of the oral matrix
`rnetalloprotelnase Inhibitor, BAY 12-9566, in
`combination with paclltaxel and Carboplatln
`
`S.G. E(~hardt1, J. Rlzzo1, C. Bdtten~, / Siu1, R. Humphra~, L. Smetzer1,
`M. Sorer~,e~-~-, P. Sundaresan2, D.D. Van Hoff1, E.K. Rowinsky~. ~
`Therapy end Research Center, San Antonio, Texas, USA; 2Bayer
`Corporation, West Haven, CT, USA
`
`BAY 12-9566 is a blphenyl nonpept~c inhibitor of zinc-dependent and(~oepti-
`dases (matdx metalloprotelnases, MMPs) that degrade the extracellular rnatdx
`end are associated with the processes of anglogenasis and metastasis m
`human malignant=as. This phase I and p~armacologic study was performed
`to evaluate the feasibility and pharmacologic Intare~on of oral BAY 12-958~
`when edmlnLaterad continuously vath Intravenous pactitaxesi and/or uarboplatln
`every 3 weeks. The study was dMded into 3 c~~secuttve cohorts of 6 patients
`(pta): 1) paditaxeel alone (course 1:175 m~n~; course 2:135 mg/rrr2), 2)
`paclltaxal (175 m.g/rrr~) and carboptatln (AUG--6), and 3) carbop~t]n (AUC--6)
`alone. Daily oral doses of BAY 12-9566 (800 rng BID) were Initiated 1 week
`following the first dose of intravar~us c~arnotherapy. Thus far, 5 of 6 pts
`(merlin age, 53 [range, 25-&9]; merlin PS, 1; pdor therapy, theme, 2; RT +
`chemo, 3) have been accrued to the first ¢ehorL Hematologic toxlcttles in~ude
`grade 1 nautropanla (1 pt) and 1 episode of grade 4 nautrot3e~ia (1 pt) lasting
`2 days. Nonhernatologic toxJcttiea have been mdd and Incfude grade 1 nausea
`and atot:~da. No dose-limiting tu~daty