ILL Number: 161473883 Regular
`I llllll lllll lllll lllll 111111111111111111111111111111111
`
`rfl
`11)
`
`Deliver Via: GZH Web PDF
`
`Call #: Q 7 AN662 ON4
`
`Location: med
`
`Full Citation:
`
`Journal Title: Annals of oncology : official journal
`of the European Society for Medical Oncology I
`
`~ ·-.........
`~ 4-< ro ___,
`·~ c _ o_ z=
`J3
`c:=
`11) =
`;> -
`Volume: 9 Issue: Suppl. 4
`.,.......=
`Month/Year: 1998 Pages: Abstract
`-~ 11)
`;;;;;;;;: o=
`609P,p.126+ TOC+cvr w/
`......... c
`N a en
`co
`.q-
`r-.
`..
`N
`z
`I-
`"C
`ns
`:::i
`..J
`
`;....._
`
`-
`
`co
`
`11)
`
`;::)
`()
`0
`0
`bl)
`c
`.........
`..0
`u.:i
`
`·-
`
`Article Author: Niyikiza et al.
`Article Title: MTA (L Y231514): Relationship of
`vitamin metabolite profile, drug exposure, and
`other patient characteristics to toxicity+ TOC+acq
`datestamp on cvr
`
`Date: 11/19/2015 918:57 AM
`
`Borrower:UIU
`Ariel: borrowing@library.illinois.edu
`Fax: 217-244-0398
`Phone: 217-333-0832
`Email: borrowing@library illinois edu
`
`Patron: Interlibrary Borrowing
`
`Comments:
`
`Need By:
`
`Maxcost:35.00IFM
`
`COPYRIGHT NOTE
`
`COMMENTS:
`
`Upon receipt of this reproduction of the
`publication you have requested, we ask that
`you comply with copyright law by not
`systematically reproducing it, or in any way
`making available multiple copies of it.
`
`Document Delivery for Non-Affiliates
`Ebling Library, Rm 3102
`University of Wisconsin. Madison
`750 Highland Avenue
`Madison, WI 53705-2221
`
`Phone: (608) 262-6362
`Fax: (608) 265-5598
`Email: eblingmls@library.wisc.edu
`Hours: Monday- Friday 7:30-4 CST
`
`UNIVERSITY OF
`
`SIN·· MADI
`
`EBLING LIBRARY
`
`HEALTH
`
`ENC
`
`Teva – Fresenius
`Exhibit 1034-00001
`
`

`
`I
`
`it?t_
`
`*
`* *
`** *
`*** *
`* * *
`* ESMO
`* * * ***
`*
`
`Volume 9, 1998
`Supplement 4
`
`CODEN ANONE2
`ISSN 0923-7534
`
`ABSTRACTS
`
`23rd Congress of the
`European Society for Medical Oncology
`
`November 6-10, 1998 - Athens, Greece
`
`]ll(!lldllL'(iOll
`
`LSi\10 Ctl111111itll'l'"
`
`.,\d,nm\kdgL'llll'll('>
`
`Spun,ur-.. and l·\liihi1t1r..,
`
`I L1111iltrn1 h1i1 In .\\\anl lur ( 'linical RL",L':trL·ll
`Im ilL'd ah-..trac\ !
`
`PrL·-.,1dL'lltia! Sy111po-..1um
`.\h..,tr~ich 2 --+
`
`l·S\10 S]K'Cial S~mpo"iu111 ··ca11LTr !nab lm\anb tliL' 1111lknniu111"
`Im ikd ah..,trach .') 7
`
`LSi\1() S[ll'C1<1I Sy111po..,1um "D11'11cult arL':tt-. i11 ly111phu111:1"
`Im 11L'd ah .... trach S l 2
`
`l·:'.'i \1()/ ·\S( '()Joint Sy 111po .... iu1n "( 'ontrm L'r'·,il''-. i11 lrl':llllll'lll or IJ()f\-',lll;tll L'L'll lung l'<llll'l'l"
`Im 1\L'd .th..,lr<tL'h l ~ 17
`
`BrL':l'>l L·:ull"l'L L'<lrly
`\h...,lr.tL"l" IX)~
`
`lhL·a-.,1 L·tull'n. ;1d\ ;rnn·d
`1--l.h
`.\h-.,tr:1ch -~-I-
`
`(';nll'i.._'r 111lhL'1.'llkth
`j )-I-
`\h,.,ll"lll"[\ 1.il)
`
`( 'ulotLTlal L"<l!ll'l'l
`,\h\\t;lL"h [)) 2])
`
`(i.t'->lrtHlllL"-.\111al 1u111our-.,
`\hqrach 217 -2(1)
`
`(iL'!l1to-uri11an t1111Hn1r'->
`1\h...,traL·h· 2<ih ~I()
`
`( i) llaL'L'OlO~-'.icll l'i\lll'l'l
`.\h-.,trach Jl2 1)1
`
`~ kad and tll'd, L·a11n·1
`-\h'->lt"aL·t.., _))...]. _1X [
`
`I .1._·uka1._'lllia and 111y1._·lorua
`i\h-.,trach ~X2 llJX
`
`111
`
`I 111
`
`I
`
`1111
`
`I ,l111g (Oral prL''L'11t;1tio11' NSCLC + SCLCi
`;\l1'trach ,\')'! 4116
`
`L1111g, NSCLC
`,\h\ll'<IL'h -f(l7-J<)(i
`Lu11~. sciJ'
`1\h..,tral'I.., ...J.l)7 ) 13
`
`l,)lllphoma
`Ah-..trnct:-. .') l--l--.'i.51
`
`l\1L'la1HH11a ;111d -..;1rc(11na
`AhslraL'I" ))2-57(1
`
`\
`
`1lolL'cular oncolof.!\
`,\h,trac1' 'i77'--'600
`
`Nll\'L'l thnaJK'utic:-. a1HI pharn1an1lll~)
`r\h-.t1;1cl'> 6()[-6(ll)
`
`Palliati\'1..' and support1vL' can:
`Al1'trach (17-l 72-l
`I nckx of author:-,
`''""''or subjects
`
`11
`
`ll
`
`7'!
`
`VI
`
`\'ll
`
`viii
`
`XI
`
`X'i
`
`1m
`
`107
`
`115
`
`1211
`
`12'\
`
`1-lO
`
`153
`169
`
`Teva – Fresenius
`Exhibit 1034-00002
`
`

`
`I
`
`~
`)
`
`(
`
`~
`
`··-
`')
`
`')
`
`'
`. •)
`, .. ,
`.
`
`>
`
`)
`>-.
`
`..
`·-
`:..!
`
`O'.:"l
`c·.
`.......
`(. .
`
`:-,.J
`c·
`(
`
`···'
`
`.__
`'
`r
`
`<Dft)
`.?.:~
`,_ (')
`0 cf)
`'- -
`'T: ·"'
`.,. :>
`c.:
`_; ·-
`")
`:.)
`c> ,:;j
`.,... :?:
`Fe
`
`l('
`
`World leaders
`
`n b otechnology
`
`Teva – Fresenius
`Exhibit 1034-00003
`
`

`
`r
`
`23rd Congress of the
`European Society for Medical Oncology
`
`No\'e111/Jcr 6-10. 1998-/\thrns, Greece
`
`Table of Contents
`
`Introduction
`23rd ESMO Congress - Organisation
`
`ESMO Comrnittccs
`
`Ac I-- now lcdgernents
`
`Sponsors and Exhibitors
`
`Abstracts
`
`Hamilton htirln Award ror Clinical Research
`In\ ited abstract I
`
`Prcsidrntial Syrnposiurn
`Abstracts 2-4
`ESMO Special Syrnposiurn ··cancer trials towards the rnilknniurn"
`lmited abstracts 5 7
`
`ESMO Special Syrnposiurn ··Diflicult clinical areas in lyrnphorna"
`Ill\ ited abstracts 8-12
`ESrvlO/ASCO Joint Syrnposium ··controversies in trcatrncnt or non-srnall cell lung cancer"
`Im itcd abstracts 1.1-17
`
`Breast cancer. early
`Abstracts 18-53
`
`Breaq cancer. advanced
`Abstracts 54-146
`
`Cancer in the elderly
`Abstracts 149-1.54
`
`Colorectal cancer
`Abstract\ 1.5.5-21.'i
`
`Gastrointestinal tumours
`Abstracts 217-26.'i
`
`Genito-urinarv tumours
`Abstracts 266-3 I()
`
`Gynaecological cancer
`Abstracts 312-3.53
`
`Head and neck cancer
`Abstracts 3.54-381
`
`Leukaemia and myeloma
`Abstracts .182-.198
`
`4
`
`11
`
`31
`
`32
`
`46
`
`.56
`
`6.5
`
`74
`
`7l)
`
`Lung (Oral presentations NSCLC + SCLC)
`Abstracts 399-406
`
`Lung. NSCLC
`Abstracts 407-4%
`
`Lung. SCLC
`Abstracts 497-.'i 13
`
`I ,ymphoma
`Abstracts .'i 14-.'i.'i I
`
`Melanoma and sarcoma
`Abstracts .'i.52-.576
`
`Molecular oncology
`Abstracts 577-600
`
`Novel therapeutics and pharmacology
`Abstracts 601-669
`
`Pal I iative and supportive care
`Abstracts 6 7 4-724
`I ndcx of authors
`I ndcx of subjects
`
`v
`
`VI
`
`VII
`
`VIII
`
`XI
`
`3
`
`83
`
`85
`
`Im
`
`107
`
`11.'i
`
`120
`
`12.'i
`
`140
`
`1.53
`169
`
`Teva – Fresenius
`Exhibit 1034-00004
`
`

`
`DOX and TXT, as already proven for Pacl1taxel + DOX leading to increased
`DOX-AUC and enhanced cardiotoxicity (Gianni et al). Therefore PK behavi01
`of both. DOX and TXT, was analyzed using 2 different tirne schedules: DOX
`50rng/rn2 30rn1n inf. followed irnrnediately (A) of alter 1 HR interval (B) by TXT
`75mg/rn 2 1 HR infusion.
`Methods: All pts received TXT alone at cycle 1 for baseline determination
`followed by DOX + TXT (18 pts schedule A. 13 pts B. sampling for both DOX
`and TXT). followed by DOX baseline analysis (12 pts A. 6 pts B. TXT then
`given delayed after end of DOX sampling). Sampling period 4HR for TXT and
`6HR for DOX. measured by HPLC, Win Nonlin noncompartimental analysis I
`performed.
`Results: of the respective AUC last:
`
`AUC
`ng/ml H
`
`A
`B
`
`TXT
`
`1484
`1703
`
`18
`13
`
`Taxotere
`
`DOX/TXT
`
`Ooxorubicin
`DOX
`DOX TXT
`
`1956
`2450
`
`0 OJ
`0.05
`
`1?
`6
`
`859
`906
`
`848
`833
`
`0 9
`0.6 .
`
`)'1
`I'•
`
`r:il
`,,
`'
`
`!.,
`' I ti
`
`. !'II,
`rn
`;':;
`:1 I
`I• I
`llJ'
`l~!I
`
`I•
`
`Conclusions: A rapid, sensitive and reliable method has been developed for
`the measurement of plasma dUrd in patients receiving antifolate drugs. These
`data suggest that the duration of TS inhibition is dose-related and will help in the
`choice of dose and schedule for Phase II trials of ZD9331 and understanding
`the relationship of duration of target inhibition and response/toxicity.
`
`16050 I Strategies for improvement in dose escalation using
`the continual reassessment method (CRM) in phase I
`clinical trials
`
`l,,.L. Siu, X. Paoletti, J. O'Quigley, E.K. Rowinsky, G.M. Clark, D.D. Von Hoff.
`S.G. Eckhardt. Cancer Therapy and Research Center. San Antonio. TX. USA
`and U436 INSERM. Paris. France
`
`The CRM has been proposed as an alternative dose escalation method in
`the phase I clinical trial design of antineoplastic agents, with the aim of
`exposing a greater proportion of patients (pts) to therapeutic drug doses than
`traditional approaches. The statistical model utilized is a sequential Bayesian
`estimation scheme in which a prior distribution function of the rnaxirnum
`tolerated dose (MTD) and a dose toxic-response model are selected before
`the trial. The MTD is the dose at which a pre-determined percentage (e.g.
`30%) of the pt population would experience dose-limiting toxicity (DLT. e.g. Gr
`3 non-hematologic or Gr 4 hematologic). In response to the practical and safety
`concerns of cytotoxic chemotherapy, modifications of the CRM (MCRM) were
`implemented which include the use of a conventional starting dose and the
`fixation of dose levels a priori, customarily by applying the modified Fibonacci
`sequence. However, our experience with this dose escalation method has
`been problematic due to the dependence on non-clinical toxicity information
`prior to the trial, and the difficulty of predicting a fixed number of dose levels.
`Therefore, we have designed a "dual-stage" escalation scheme. The initial
`stage involves utilization of a conventional starting dose with doubling of the
`dose in single-pt cohorts until moderate toxicity (e.g. Gr 2 non-hematologic or
`Gr 3 hematologic) is encountered, at which point 2 additional pts are accured
`and dose escalation proceeds in a more conservative manner (e.g. at 33%
`to 50% increments). The second stage begins once DLT is reached. and the
`CRM is used to guide subsequent assignment of dose levels. Instead of the
`Bayesian methodology, a maximum likelihood approach (O'Quigley and Shen)
`is applied which offers greater flexibility without restriction by the paucity of
`prior data. Practical examples and simulations of models will be provided to
`illustrate this proposed dose escalation method .
`
`\ 6060 \ Synergistic antitumor effect by novel modified
`oligonucleotides targeting PKAI combined with
`cytotoxic drugs or monoclonal antibodies
`~ortora, V. Damiano, R. Bianco, S. Pepe, A.R. Bianco. S. Agrawal 1
`.
`J. Mendelsohn 2 , F. Ciardiello. Oncologia Medica. Univ.Federico II. Napoli,
`Italy: 1 Hybridon, Cambridge. MA, USA; ?UT-MD Anderson Cancer Center.
`Houston. TX. USA
`
`Introduction: Protein kinase A type I (PKAI) plays a key role in neoplastic
`transformation and conveys mitogenic signals of different growth factors and
`oncogenes. Moreover, PKAI is overexpressed in cancer cells with an active
`TGFu-epidermal growth factor receptor (EGFR) autocrine pathway and shows
`a structural and functional interaction with EGFR. Inhibition of PKAI, or its
`regulatory subunit Rlu. results in cancer growth inhibition in vitro and in vivo.
`Methods: A novel class of rnixed backbone oligonucleotides (MBOs) tar(cid:173)
`geting PKAI (ASRlu), with improved pharmacokinetic and bioavailability, and a
`humanized monoclonal antibody which blocks activation of EGFR, MAb C225,
`have been tested in vitro and in vivo on several human cancer cells.
`Results: A dose-dependent inhibition of soft agar growth was obtained in
`all cancer types tested with the AS RI" MBOs. as compared to mismatched
`control oligos. Non-inhibitory doses of each MBO resulted in a synergistic
`growth inhibition and increased apoptosis, when combined with taxanes,
`platinum-derivatives and topo II-selective drugs. When the MBOs administered
`either i.p. or p.a. were added to paclitaxel, a cooperative effect was also
`obtained in vivo. causing tumor growth inhibition and increase of survival in
`nude mice bearing human cancer xenografts. Finally, combined treatment of
`human breast and renal cancer cells. which overexpress PKAI and EGFR,
`with the ASRI" MBO and MAb C225, caused a cooperative antitumor effect m
`vitro and in vivo.
`Conclusions: Since both the AS Rb MBOs and the MAb C225 are currently
`studied in clinical trials. the combination between them or with selected
`cytotoxic drugs rnay represent a feasible novel therapeutic strategy.
`
`\ 6070 J Pharmacokinetic (PK) interaction of the combination
`of doxorubicin (DOX) and Taxotere (TXT)
`
`)_.Schull~. M. Czejka, E. Krexner, K. Lehner, H. Bucher, G. Schernthaner.
`Hospital Rudolfstiftung Oneal. Dep., lnstit. pharma chem Vienna. Austna
`
`Introduction: Combination of DOX with TXT has been shown to be highly
`effective in advanced breast cancer recently introduced into adiuvant treatment.
`Purpose of the present study was to detect a potential PK interaction between
`
`Conclusion: No influence of TXT on DOX-AUC documented. DOX-ol cone 1
`(n=8) with or without TXT n.s. different (p 0 2 - 0.8). thus explaining low ,
`1
`card1otoxic1ty of the combination. In contrast. TXT-AUC was s1gnif1cantly 1n-'
`creased when combined with DOX, suggesting interference at the hepatic
`microsomal level, partly explaining high clinical efficacy. A 1 HR delay between 1
`end of DOX and start of TXT does not change the respective PK behaviour ol I
`both drugs.
`
`\ 608P I Gemcitabine (GEM) - cisplatin (COOP): A schedule
`finding phase I/II study
`J.R___Kr0.E'Q 1 , G.J. Peters', C.J.A. Van Moorse1 1 , J.B. VermorkenJ
`. H.M. Pinedo 1. C.J. Van Groeningen 1
`1 Dept Oneal
`P.E. Postmus", A. Catik 1
`and 2 Pulm., Univ. Hosp. VU. Amsterdam. NL and 3 Dept. Oneal.. Univ. Hosp.
`Antwerp. B. The Netherlands
`
`Introduction: Gem and CDDP are active against various solid tumors. Since I
`preclinical studies demonstrated the efficacy of various schedules we evaluated
`the tolerability and clinical efficacy of 4 different Gem/CDDP sched. ules as pan r
`of a pharmacok1netic and -dynamic (PK/PD) study.
`Methods: Gem 800 mgim" was administered as a 30 min 1nfus1on on d 1. 8.
`15. and CDDP 50 mgirn" over 1 hr on d 1. 8 every 28 days: Gem 4 hr before
`CDDP (1 Opts), or vice versa (14) and Gem 24 hr before CDDP (9). or vice versa
`(9). after one cycle followed by the reversed schedule. Pts (19 male/23 female
`median age 54 years [31-77]. and performance status 1 [0-2]) included. 9
`ovarian, 7 non-srnall cell lung (NSCLC), 5 head/neck squamous cell (HNSCCI
`5 esophageal. 4 melanoma. 4 cervix, 3 adenocarc1noma. 2 pancreatic. 2 colon
`and 1 small cell lung (SCLC). 26 pis received poor chemotherapy. of which 21
`platinum based.
`Results: A mean of 4.2. 2.6. 3.8 and 3.5 cycles was given 1n the four
`schedules. resp. The most frequent overall grade 3/4 CTC-tox1c1ty was throm(cid:173)
`bocytopenia, 6/10. 4/14. 2/9 and 6/9 (overall 60°0). followed by leukopenia
`8/10, 5/14. 6/9 and 6/9 (43°~). in the 4 schedules. resp Therefore. Gem was
`not given on d 15 in 36% of pis in cycle 1 Anemia was observed 1n 64',
`of pis. No serious bleeding occurred. Myelotox1c1ty was cumulative. but nol
`schedule dependent. Non-hematological toxicity consisted mainly of grade 12
`nausea/vomiting and fatigue. One patient died of toxicity following severe neu·
`tropenia and sepsis. Creat1nine clearance decreased slightly durrng therapy
`Anti-tumor effects in 36 evaluable pts: HNSCC. 1 CR: esophageal. 1 CR/2PR
`ovarian, 2 PR: NSCLC. 1 PR: melanoma. 1 PR and adenocarc1noma. 1 PR
`Conclusion: (Cumulative) myelosuppression was the ma1or toxicity, al·
`though it was not schedule dependent. Based on toxicity. efficacy and PK/PD
`data a phase II study. CDDP 24 hr before Gem, has been started in pts with
`upper gastro-intest1nal tumors
`
`[ 609P [ MTA (LY231514): Relationship of vitamin metabolite
`profile, drug exposure, and other patient
`characteristics to toxicity
`~Niylti_za, S. Baker, R. Johnson. J. Walling, D. Seitz, R. Allen Lilly Researc~ 1
`Laboratories, Indiana. USA: Cancer Treatment and Research Center. Texas.
`USA; Univ of Colorado Health Sciences Center. Colorado. USA
`
`Introduction: MTA 1s a novel multitargeted antifolate with inhibitory act1v1ty
`against multiple enzymes. Phase I/II studies have shown activity 1n a varrely
`of tumors. Historical data on other antifolates have suggested that a patients
`nutritional status may play a role in the likelihood of experiencing severe toxicity
`The purpose of this study was to assess the relationship of vitamin metabolites
`drug exposure, and other prespec1fied baseline patient characterrst1cs to tox1c1ty
`following treatment with MTA.
`Methods: Homocysteine (Heys), cystath1onine and methylmalonic acid were
`measured 1n 139 phase II patients with tumors of the colon, breast. pancreas
`and esophagus at baseline and once each cycle thereafter. Stepwise regres·
`sion modeling. multivariate analysis of variance. and d1scrrm1nant analysis
`were implemented to determine which predictors rn1ght correlate with severe
`toxicity after one course of MTA. Prognostic factors considered were age. ger·
`
`126
`
`1\11n11f.\ 11(01u ulo/.!,\·. SuppklllL'Hl -1- tu Volt1nlL' l)_ \l)l)X
`
`1
`
`\')l)X Kh1\\L'I ,\1.·<1d1.:111iL' Puh!i"hL'l'-. P11n\l'd 111 TllL' :-.L'lhL·ilan1I'
`
`Teva – Fresenius
`Exhibit 1034-00005
`
`

`
`der. prior treatment, baseline albumin. liver enzymes, ANC, platelets, vitamin
`metabolites. and AUC.
`Results: Stat1st1cally sign1f1cant predictors of Grade 4 neutropenia (n=21
`pts) were albumin (p = 0.0006) and Heys (p = 0.0012), while Grade 4
`0.0001) and
`thrombocytopenra (n=8) was highly predicted by Heys (p
`pre-treatment AST (p = 0.0012). Heys
`10;1M predicted Grade 4 neutropenia
`in cycle one 75°0 of the time. Grade 4 neutropen1a was predicted by Heys
`alone in 70°0 of cases. Heys and albumin levels did not appear to change
`from baseline during treatment with MTA. While AUC was not found to be a
`predictor of tox1c1ty, little variab1l1ty was observed in AUC. Maximum values
`were still below AUC values related to hematologic toxicity in phase I studies.
`Conclusions: Tox1c1ties resulting from treatment with MTA appear to be
`predictable from pretreatment homocyste1ne levels. Elevated baseline ho(cid:173)
`mocyste1ne levels (_ 1011 M) highly correlate with severe hematologic and
`nonhematologic tox1cit1es following treatment with MTA. Homocysteine was
`found to be better than albumin at pred1ct1ng toxicity. These results apply to
`the tumor types studied. Further studies are underway in patients with renal
`1mpa1rment or patients who received prior cisplatin.
`
`] 610~ Phase I and pharmacokinetic (PK) study of Tomudex
`·
`(TOM) + 5-Fluorouracil (5-FU) and levofolinic acid (LFA)
`in advanced head and neck and colorectal cancer
`E_~_aponigrcl. R. Casaretti. HL Mcleod 1
`. A. Budillon, G. Carteni, F. De Vita,
`A. Avallone. M. Bigl1etto. A. Tucci. J. Morsman 1 . D. Barbarulo, G. Catalano,
`P. Comella. G. Comella. Southern Italy Cooperative Oncology Group c/o
`Natwnal Tumor Institute of Naples. ITALY: 1 University of Aberdeen, UK
`
`Background: Synergism between TOM and 5-FU + LFA is observed 1n vitro
`when cells are exposed lor 24 hours to TOM, followed by 5-FU + LFA.
`Precl1nrcal studies support the idea that TOM might down-regulate the activity
`of d1hydropyrimidine dehydrogenase (DPD).
`Patients and methods: Patients (pts) with advanced head and neck and
`colorectal cancer were treated with escalating doses of TOM on day 1, and
`bolus 5-FU (immediately after LFA) on day 2, every 2 weeks. In the 2"d course
`LFA and 5-FU were administered on day 1 and TOM on day 2 with the aim
`of evaluating DPD and 5-FU AUC with and without pretreatment with TOM.
`Further treatment was given according to the sequence used in the 1st course.
`Results: Available clinical data are summarized below.
`
`Step
`
`TOM'LFASFU (mg:rn 2 )
`
`Pts
`
`C.HN' DLT
`
`Type'
`
`Response
`
`1 5 250 600
`2 0 250 600
`2 0 250750
`2 5 250 750
`2 5'250'900
`3 0'250 900
`3 0•250 1050
`30250.1200
`
`6
`6
`
`6
`
`16
`
`58
`
`115
`5;1
`5/1
`511
`611
`8/0
`917
`2·1
`41.17
`
`0/0
`016
`016
`016
`017
`1/8
`3.'15
`23
`
`0/6
`116 (PR)
`1/6 (PR)
`3/G (2CR, 1 PR)
`017
`1/8 (CR)
`6/13 (1CR. 5PR)
`1/3(PR)
`OR
`
`N 4
`N 4: N 4. N 4
`N4.M3;R3
`
`Tota1
`
`'Co- colorectal cancer: HN head & neck cC1ncer. C = 6/39 (15°0). HN = 7/16 (44°0), N =
`neutropcm1 M = rnucosit1s R =- Renal
`
`DPD act1v1ty has been measured 1n 14 pts thus far. Pretherapy DPD activity
`was a median 34°0 higher than after TOM administration (95% C.I.
`93 to
`+62°0). PK data are available tn 6 patients thus far. and 5-FU AUC basal
`values do not s1gn1ficantly differ from values obtained 24 hours after TOM.
`Conclusions: The combination of TOM+ 5-FU/LFA is well tolerated every
`2 weeks. Clinical act1v1ty looks very encouraging, since the majority of pts had
`already received prior chemotherapy. We are now treating some additional
`chemo-na1ve patients at step 7, 1n order to have a more reliable estimate of
`the act1v1ty of the regimen.
`
`~ Radio-localization of pulmonary nodules using
`gamma-probe and resection by video-assisted
`thoracic surgery
`, G. Grosso 1
`A. Chella. G.F. Menconr. F.M.G. Melfi. A. Gonfiotti, G. Boni 1
`E:f3~1dini 2 . C.A. Angeletti. Service of Thoracic Surgery. Department of
`Surgery. 1 Service of Nuclear Medicine and 2 Service of Medical Oncology.
`Department of Oncology. University of Pisa. Italy
`
`•
`
`V1deo-ass1sted thoracic surgery (VATS) 1s emerging as safe procedure for
`diagnosis and treatment of peripheral pulmonary nodules. One limitation of
`thoracoscopic technique is the inability to detect those nodules which are very
`deep beneath the pleural surface. and could only be identified via manual
`palpation. Several methods are used to localize VATS occult lesions prior to
`exc1s1on. including methylene blue 1n1ect1on and introduction of hooked-wire:
`however. all suffer from l1m1tations. Recent advancements in intraoperative
`radio-localization of non-palpable breast lesions prompt us to develop a new
`technique for detection of pulmonary nodules by VATS. CT-scan are used
`to guide perilesional injection of 0.2
`0.5 ml of solution of 99m Tc-labeled
`human serum albumin m1crospheres (5--10 MBq) and 0.2 ml of iodine-non-ionic
`contrast medium. two hours before surgery. In VATS a gamma ray detector
`(Scint1 Probe MR 100 - Pol.hr.tech .. Aquila. Italy). equipped with 11 mm
`
`No1'cl thcmpcutics and pharmaco/ogr
`
`diameter-collimated probe, allowed us to locate that lesion for thoracoscopic
`resection. From June 1997 to January 1998 we treated 15 consecutive patients
`(pts) with sub-centimeter pulmonary nodules. Nine pts were affected by a
`synchronous and metachronous malignant neoplasm in other sites. Computed
`thomography of the chest helped in the planning of the operative procedure, the
`position of pts, and ideal ports. A hot-spot was easily detected. in all patients,
`by the probe introduced in the pleural space through a 11.5 mm trocar. The total
`excision of the lesion was confirmed by detection of radioactivity in the removed
`specimen and its absence in the resection margins of the lung. Pathological
`examination of specimens showed 8 benign lesions and 7 malignant lesions
`(4 metastases and 3 lung cancer) and it confirmed the absence of infiltration
`in the resection margins. The surgical procedure was extended for an average
`of 56.6 minutes (range 35-100 min). The average post-operative hospital stay
`was 3.6 days (range 3-6 days). In our experience this technique proved safe
`and accurate, allowing easy detection of the pleural surface projection and fast
`removal of the lesion. This technique offers a simple and reliable method for
`localization of primary and metastatic tumors by VATS.
`
`j 612P j Pharmacokinetic (PK) of Tomudex" (raltitrexed) (T)
`and oxaliplatin (0) combination: Preliminary results of
`an ongoing phase I study
`, M. Bonnay 1
`, D. Fourcault 1
`. P. Ruffie 1
`K, Fizazi 1
`, 0. Couturas2 , M. Smith 2 ,
`R. Gomeni 2
`, A. Fandi 2
`, J.P. Armand'. 1 lnstitut Gustave Roussy, Villejuif,
`2 Zeneca Pharmaceuticals, Cergy. France
`
`Introduction: The aim of this study was to evaluate the possible kinetic
`interactions between T and 0 administered to patients with advanced disease.
`Methods: Patients first received T (15 min infusion), followed 45 minutes
`later by 0 (2-hour infusion). Three patients received Tat a dose of 3 mg/m2
`and 3 at a dose of 3.5 mg/m 2 . All of them received the same dose of 130
`mg/m 2 of 0.
`Results: Plasma concentrations of T declined tri-exponentially after the
`end of the infusion. The terminal t1/2 derived from samples up to 28 hours
`post-dose varied between individuals from 9.3 to 193.2 h with average values
`of 73.4 and 33.7 for the two dose levels. The maximal concentrations varied
`between 323 and 1185 ng/ml with averages of 681 and 813 in the 3 mg/m2 and
`3.5 mg/m2 groups respectively. The AUC varied 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 difference, probably due to the very large
`intra subject variability, however the mean AUC showed an approximately
`proportional increase with increasing dose. The estimated kinetic parameters
`were in agreement with the values previously published. Plasma concentrations
`of O declined bi-exponentially after the end of the infusion. The terminal t1/2
`varied from 18 to 30 h (average of 25). Cmax ranged from 3.13 to 4.53 (average
`of 3.69) ;1g/ml. The AUC ranged from 74 to 120 (average of 195) ;1g.h/ml and
`the Cl varied between 1.76 and 3.43 (average of 2.47) 1/h. The comparison
`of the kinetic parameters of 0 to the ones previously published in the same
`experimental conditions seems to indicate that T induced an increase of 0 Cl
`(from 1.32 to 2.47 1/h) with a reduction of the terminal t1/2 from 38.7 to 24.8
`h and a reduction of Cmax measured at the end of the infusion from 5.11 to
`3.69 11g/ml.
`Conclusions: These preliminary results suggest that the expected concen(cid:173)
`trations of 0 obtained after administration of T may be lower that the ones
`observed when 0 is administered alone. These results indicate possible PK
`interaction between the two drugs.
`
`] 613P I A phase I and pharmacokinetic (PK) study of ET-743, a
`novel minor groove binder of marine origin
`administered on a daily x 5 schedule
`M. Hidalgo, M.A. Villalona-Calero, S.G. Eckhardt, G. Weiss, E. Campbell,
`M. Kraynak, J. Bei1nen, J. Jimeno. D. Von Hoff, E. Rowinsky. Cancer Therapy
`and Research Center, San Antonio, TX, The Netherlands Cancer Institute,
`Amsterdam. The Netherlands: PharmaMar, S.A.. Madrid, Spain
`
`ET-743 is a novel tetrahydroisoquinoline alkaloid isolated from the marine
`organism Estenaiscidian turbinata which binds to adenine-cytosine rich regions
`within the minor groove of DNA. This study is evaluating the feasibility and
`PK behavior of ET-743 administered as a 1-hour infusion daily x 5 every 3
`weeks in patients with advanced solid malignancies. Twenty-seven patients
`(median age 58, range 35-79: median ECOG PS-1) have received 67 courses
`of ET-743 at doses ranging from 6 to 380 ;1g/m2 /day. At the 380 ;1g/m,day
`dose level, 1 patient with extensive prior treatment with 16 cycles of BCNU
`developed grade 4 thrombocytopenia. grade 4 neutropenia with fever, grade
`3 elevation in transaminases, and acute renal failure which resulted in death.
`Four patients (8 cycles), at the 216 (1), 287 (1) and 380 (2) ;1g/m2 /day dose
`level developed asymptomatic elevation in hepatic transaminases of grade
`3 severity that typically peaked on day 8 and resolved by day 21. Mild to
`moderate. dosedependent nausea and vomiting, which appeared on day 4
`and resolved on day 8, was observed in 14 patients. Two patients at the 380
`11g/m.2 /day dose level suffered superficial venous thrombophlebitis at the drug
`1nfus1on site. PK parameters obtained in 2 patients at the 216 11g/m2 day dose
`level included: clearance, 137 and 589 mUmin/m,: t,
`, 13.7 and 23.1 Uh; and.
`
`Teva – Fresenius
`Exhibit 1034-00006