`
`,
`ESO
`European School of Oncology
`EACR
`
`
`
`
`
`ECC_C_) 11
`
`the European
`Cancer
`
`Conference
`
`‘C.
`
`.___..__—""‘*J:“‘"—"'We
`
`The Ofi‘iciaijoumoi of
`
`EORTC
`
`European Organization for
`Research and Treatment of Cancer
`
`European Association for
`Cancer Research
`
`FECS
`
`Federation of European
`Cancer Societies
`
`EUSOMA
`
`European Society of Mastology
`
`West-Ward Exhibit 1031
`Boni 2001
`
`Page 001
`
`West-Ward Exhibit 1031
`Boni 2001
`Page 001
`
`

`

`S68
`
`Monday
`
`22 October
`
`2001
`
`surgery
`
`for MoPBC,
`
`T, Ndemethyi
`circulating
`studied
`the Study: We prospectively
`Aim of
`and 4-OH-T)
`that
`to be
`(D-T, DD-T
`T, N-dedimethyl
`T and Chydroxy
`T
`steroid
`hormone
`binding
`matched
`with
`lipids,
`coagulation,
`blood counts,
`globulin
`(SHBG),
`various
`hormones,
`vaginal
`katyopyknotic
`index
`(KPI)
`(our
`previous
`studies
`BMJ
`ii: 1351-2,
`1977; Cytopatol
`9: 263-270,
`1998) and
`transvaginal
`ecosonography
`endometrial morphology.
`Patients
`were 85, consecutively
`enrolled after
`radical
`and given adjuvant
`T 20 mg/day
`for 5 years.
`effects within 2 w.s
`Results:
`T induces most of
`its agonist
`estrogen-like
`therapy.
`A steady
`state of
`the biological
`events
`is reached
`in about 4 w.s
`and persists
`up
`to 60 mo.s. Cholesterol,
`LDL-C,
`HDL-C,
`LDL-CiHDL-C
`ratio, apolipopmtein
`B/apolipoprotein
`A ratio,
`fibrinogen
`and antithmmbin
`Ill activitv
`droooed
`from 2 w.s
`to 60 mo.s. HDL-C was unchanged.
`SHBG
`and KPl~incr&ed
`early, while FSH, LH and prolactin
`decreased.
`A late
`rise of Hb, PCV occurred
`from
`the
`lSti mo. Platelets were
`lower
`from
`the
`4”’ w (all quoted
`results:
`p 5 0.005).
`Plasma
`concentration
`of T and
`its
`metabolites
`shows
`interpersonal
`variations;
`the steady
`state was
`reached
`at the 4@’ w. Positive
`relations
`(p 5 0.005)
`existed
`between
`4-OH-T
`and
`fibrinogen
`and KPI,
`inverse
`relation
`between
`4-OH-T
`and antithrombin
`Ill,
`D-T and
`fibrinogen,
`DD-T and
`fibrinogen.
`Agonistic
`properties
`are mainly
`exerted
`by the
`three metabolites.
`Further
`analyses
`is ongoing.
`In praise
`of GOCNE
`(Giuppo
`Onwlogiw
`Cooperativo
`Nor&Est),
`Aviano
`(PN).
`Italy This
`investigatibn
`is part of the study pmgrama
`partia//y
`supported
`by AOI-Asaociazione
`Onwlogica
`Italiana, Aviano
`/ta/y
`
`CR0
`of and
`(PN),
`
`240
`POSTER
`two different
`using
`(PK) of irofulven
`Pharmacokinetics
`intermittent
`dosing schedules as a 90’minute
`(MN)
`infusion
`in advanced
`solfd
`tumors
`(AST): Preliminary
`data
`F. Lokiec’,
`E. Raymond2,
`J. Alexandre3,
`E. Brain’, M. Ould Kaci4,
`f Center
`S. Lagree4,
`S. Smith’,
`K. Vanderbilt’,
`E. Cvitkovic4,
`J.L. Misseta.
`Rent? Huguenin,
`Saint-Cloud;
`21nstitut Gustave-Rouss)$
`Wilejui~ 3 H6pital
`Paul Brouase,
`Viliejuif 4 CAC, Kremlin-B&We,
`France;
`5MGl Pharma,
`Minnesota.
`USA
`
`promis-
`analog of illudin S, has shown
`an acyifulvene
`Irofulven,
`Purpose:
`during
`preclinicaUdinical
`development,
`with delayed
`ing anti-tumor
`activity
`thrombocytopenia,
`severe
`asthenia
`and nausea/vomiting
`as treatment-lim-
`iting toxicities
`(tox). PK analysis
`of the 5 min daily x 5 or intermittent
`weekly
`dosing
`q3 or 4w schedules
`(sch)
`has shown
`a short mean plasma
`half-life
`(t1/2)
`range:
`4-8 min, with a
`large
`interpatient
`(pt) variability.
`A 30 min
`administration
`dot-responds
`to approtimately
`5 tl12. Therefore,
`by the end
`of a 30 min
`infusion,
`a steadystate
`will be reached. Within
`the ongdng
`Phase
`I study, we decided
`to use
`the 30 min
`infusion
`to improve
`the PK and
`phhrmacodynamic
`(PD) analyses
`and
`to
`investigate
`a possible
`corralatfon
`between
`observed
`tox and Cmax.
`(sch)
`schedules
`the same
`with
`treated
`,Mefhods:
`Pts with AST were
`previously
`explore&with
`the 5 min
`infusion
`duration
`I@: Di, 8, q3w and
`C: Di,
`15 q4ti)
`using
`the
`following
`dosing
`levels
`(DL
`in [mgYir?/d]).
`Sch
`B: Di2[78j;
`DL3
`[Zfi
`Sch C: Dl2
`[24], DL3
`[28j. During each pt’s
`first 3
`infusions,
`10 plasnia
`samples
`were
`collected
`up to 5 ,hours
`post-infusion.
`As of 04/2001
`I24 @s were
`included
`in Dl2 and DL3 of both sch,
`&sults:
`PK analysis
`has been performed
`for day 1 in the
`first 17 pts.
`Total body clearance
`appeared
`stable up to 28 m.
`
`DOSS
`ms/m2
`16
`21
`24
`26
`
`Sch
`W
`B(M)
`B(DL3)
`cm.3
`C (DL3)
`
`N
`eval. pts
`7
`2
`7
`1
`
`max
`rig/ml
`112*56
`115f4
`202 i 161
`214
`
`AUC
`ng/mlxh
`36.8 * 16.1
`35.9 * 1.4
`66.7 i 61.6
`70.3
`
`Cl~W8IlCCi
`Vh/m2
`566 * 279
`586123
`532 * 293
`396
`
`T,n beta
`‘min
`7.1 h 3.6
`1.9fO.l
`6.5 + 6.6
`4.7
`
`total bodv clear-
`that AUCs and
`show
`results
`Preliminarv
`Conclusions:
`is administered
`as a 5 or a 30-minute
`antes
`are similar when
`irofulven
`half-life.
`Fully updated’ PK analysis
`and
`infusion,
`despite
`its short
`terminal
`the PWPD
`relationships
`will be presented.
`
`Poster Sessions
`
`POSTER
`(GEM)
`between gemcitabine
`interactions
`(VNR) in patients wtth advanced stage solid
`
`241
`Pharmacokinetic
`and vlnorelbine
`tumors
`M. Airoldi’,
`L. Catte12.
`2 University
`
`S. Marchionatti’,
`E. Buffa2, MC. Veriengo’,
`S. Novello2,
`A.S. Hospital, Medical Oncology,
`Turin,
`Italy;
`’ S.Giovanni
`of Turin, Postgtaduate
`School
`in Clinical Pharmacy;
`Turin,
`
`Italy
`
`in patients with
`GEM and VNR are both active as single agents
`Purpose:
`stage of solid
`tumors.
`Because
`of their different mechanism
`of
`advanced
`action,
`good
`tolerability
`and
`feasible
`administration
`on an outpatient
`basis
`they should be an interesting
`combination
`for palliative
`chemotherapy.
`The
`aim of
`this
`study
`is
`to determine
`possible
`pharmacokinetic
`interactions
`between GEM and VNR.
`lung cancer
`non small cell
`Methods:
`A total of 11 patients with advanced
`or metastatic
`breast
`cancer weie
`treated with GEM
`(1 h i.v. infusion,
`1000
`mg/m2)
`followed
`by VNR
`(10 min
`i.v. slow bolus,
`15 mg/m2)
`on days ~1,
`8, every
`3 weeks;
`5 patients
`received
`single-agent
`GEM
`(lh
`i.v.
`infusion,
`1000 mg/m2)
`as a control
`group. GEM and VNR were measured
`in blo0d
`samples
`taken
`at several
`time points
`after
`the starting
`of treatment
`and
`immediately
`added with enzymatic
`inhibitor
`of deaminase
`THU.
`Plasma
`levels were quantified
`by
`liquid extraction
`followed
`by HPLC analysis
`and,
`pharmacukinetic
`data were processed
`by KineticaTM
`1 .l computer
`program
`Results? In
`the
`schedule
`GEM+VNR
`average
`Cmax
`of GEM was
`26278f4671
`@ml,
`AUC=20305f3111
`@ml/h,
`Utot=75,48+14,56
`vh,
`11/2alfa=5.1~5,3
`minJ1/2beta=18.2f3.4
`min. Thesteadv
`state was
`reached
`about
`30
`.min after &e beginning
`of administration;
`&ax
`of VNR was
`8131387
`rig/ml, AlJC=224+75
`w/ml/h,
`Cltot=192,74f72.51
`l/h; Cmax of
`single-age&
`GEM was 29295f5681
`@ml,
`AUC=24327&7346
`nq/ml/h,
`Cltot=75,20&17,78
`I/?I, t1/2alfa=3,0f5,1
`min,
`t1/2beta=20,0f5,2
`min.
`Conclusions:
`Cmax, AUC and Cl values of GEM
`followed
`by VNR agreed
`with
`the values
`shown
`in monotherapy;
`Cprt curve
`for GEM
`in combination
`was best describti
`by a biphasical model with a rapid distribution
`and elimi-
`nation. Cpii curve
`for VNR showed
`rapid distribution; moreover,
`interpatient
`variability
`was
`important
`for all parameters
`in accordance
`to the
`literature
`data;
`these prelimirlaty
`data have shown
`that
`treatment
`with GEM+VNR
`do
`not alter
`the pharmacokinetic
`behaviour
`of both drugs
`compared
`with single
`agent
`therapy.
`Further
`investigation
`is needed
`to
`relate pharmacokinetic
`data
`to toxicity
`of the treatment.
`
`of 5-fluorouracil
`the pharmawkinetics
`in ‘combination
`to patients with advanced
`
`(5-FU)
`solid
`
`and
`tu-
`
`POSTER
`
`In
`doses of Ccl-779
`and leucovorln
`In patients
`
`242
`of escalating
`Pharmacokinetics
`combination
`with 5-fluorouracil
`with advanced
`soli+
`tumors
`J Bon?
`J. Korth<Bradley’,
`C.J.A. Punt2, A. Hanauske3,
`is
`Research,
`K. Weigang-KBhleti,
`C. Thielert5,
`J. Frtsch5.
`’ weth-Aye&
`Clinical Pharmawkinetics,
`Radnor, PA, USA; 2 University Medical Center
`Nvmegen,
`The Netherlands;
`3 Onkologische
`Tagesklinik, Munich,
`Germany;
`4 Klinikum Nuemberg,
`Nuernberg,
`Gennany;
`5 Wyeth Onwlm
`Munich, Germany
`Purpose: To evaluate
`Ccl-779,
`administered
`mors.
`cycle. Dur-
`of a 7-week
`6 weeks
`spanned
`treatment
`Weekly
`Methods:
`infusion
`of
`cycle,
`a 1 hour
`intravenous
`(IV)
`treatment
`ing day 1 of each
`infusion
`200 mg/m2
`leuwvorfn
`(LV) was
`followed
`by a 24 hour continuous
`of 2600 mgIm2
`5-FU.
`Starting
`on cyclel/day
`8, 15
`to 75 mg/m2
`of
`IV
`Ccl-779
`preceded
`LV&FU
`treatment.
`Concentrations
`of 5-FU were mea-
`sured
`throughout
`the 24 hour
`infusion
`p@qd
`in cycle
`l/weeks
`1, 2 and
`4; Ccl-779
`and
`its prima@ mqtabdiite
`siiolimus
`(rapamycin)
`were
`followed
`for 8 days during
`cycle
`l/weeks
`i and 4. Parameters
`were derived
`using
`nonwmparlmental
`methods.
`Results: For 15 patients, mean&SD
`plasma mcen-
`5-R)
`steady-state
`and 666f248
`ng/mL
`tratfon was 667XZ.X
`ng/mL
`(Week
`1 without Ccl-779)
`(Week
`2’with Ccl-779);
`mean clearance
`(CL) was 326+113
`Uh
`(Week
`2).
`For 13 patients, mean Ccl.779
`CL
`increased
`with
`increasing
`dose’(13
`L/h
`[low dose]
`to 41
`I&I
`[highest’dose]
`(CV 5 30%). Mean half-life was 17&4
`hours.
`The mean
`ratio of Sirglimtis-to-CCI-779
`AUC was 2.4
`to 3.8. No
`period effects wemobserved.
`did
`regimen
`CFURV
`in the standard
`of 0X-779
`Condusioq:
`Inclusion
`not ‘affect 5-FU phatmawkinetlc
`disposition,
`nor did 5-FU change Ccl-779
`phannswkinetic
`parameters.
`
`West-Ward Exhibit 1031
`Boni 2001
`Page 002
`
`