AHHALS OF OHCOLOGY - EHGLISH EDITION
`
`o 2000 VOLUME 11 ISSUE 4 SUPPLEMEHT
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`SMO
`
`Volume 11, 2000
`Supplement 4
`
`CODEN ANONE2
`ISSN 0923-7534
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`LIBRA~:t f
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`Hamburg. Germany. 13-17 October 2000
`
`Guest Editors: Scientific Comm ittee of the 25th ESMO Congress
`
`Introduction
`25th ESMO Congress - Organisation
`ESMO Committees
`Acknowledgements
`Industrial Satellite Symposia
`Exhibitors
`
`Hamilton Fairley Award for Clinical Research
`Presidential Symposium
`ESMO Special Symposium:
`Cancer vaccination
`ESMO Special Symposium:
`Combined modality: Its present status
`ESMO Special Symposium:
`Design and analysis of clinical trials
`ESMO Special Symposium:
`Haematology: Hot spots
`ESMO Special Symposium:
`I lcrcditary preui~pu!>itiu11
`ESMO Special Symposium:
`Novel targets for cancer therapy
`ESMO/ASCO Joint Symposium :
`Chemoprevention and screening of prostate and
`breast cancers
`Angiogenesis
`Basic science and bench to bed~ide (lab)
`
`v
`VI
`vii
`ix
`XIV
`xiv
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`3
`4
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`5
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`5
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`6
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`6
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`7
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`7
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`9
`I 0
`11
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`Breast cancer. earl y
`Breast cancer (early and advanced)
`Breast cancer, advanced
`Cancer vaccination
`Colorectal cancer
`Colorec tal cancer and other gastrointesti nal tumours
`Upper gastro intestinal tumours
`Elderly patients
`Genito-urinary tumours
`Gynaecological ca ncer
`Head and neck cancer
`Leukaemia and myeloma
`Lymphoma
`Lung cancer
`Biological factors in lung cancer
`Melanoma and sarcoma
`euro-oncology
`ovel therapeutics and phamiacology. biological
`approaches
`Palliative and supportive care
`Oncology Highlights 2000
`
`Index of Authors
`Index of Subjects
`
`ESMO Application for Membership
`
`16
`22
`25
`41
`43
`59
`62
`72
`73
`81
`90
`95
`98
`107
`124
`125
`131
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`132
`145
`155
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`157
`175
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`195
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`111
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`11
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`1111
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`0923-7534(2000)11 +4;1 -0
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`Kluwer Academic Publishers
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`West-Ward Exhibit 1080
`Hidalgo ESMO 2000 - Page 001
`
`

`

`Novel therapeutics and pharmacology, biological approaches
`
`We are now conducting a phase I tnal of adenov1rally delivered nitroreductase
`and IV CB1954 in patients with primary/secondary liver tumours.
`
`I 608PD I Phase I and pharmacokinetic study of BIBX 1382, an
`
`EGFR inhibitor, as continuous daily oral
`administration.
`Christian Dittrich 1 , Uta Bruntsch 2 , Markus Bomer 3 , Karin Weigang 2 ,
`Holger Huisman•, Andree Amelsberg 5 , Jant1en Wanders 4 , Axel Hanauske 6 ,
`Pierre Fumoleau 7 . 1 LBl-ACR VIE, KFJ-Sp1tal, Vienna, Austna; 2 5th Medical
`Clime, Nurnberg, Germany, 3 Dept. Oncology, lnselsp1tal, Bern, Switzerland;
`4 NDDO-Oncology, Amsterdam, Netherlands; 5 Boehringer Jngelheim,
`Biberach, Germany; 6 Techmcal University, Munich, Germany; 7 Centre Rene
`Gauducheau, Nantes, France, For the EORTC-Early Clinical Studies Group
`(ECSG)
`
`The pyrim1do-pynmidine BIBX 1382 inhibits the intracellular tyrosine kinase
`domaine of the epidermal growth factor receptor (EGFR), thus specifically
`reverting the aberrant enzymatic act1v1ty from overexpressed and constitutively
`activated EGFR, respectively. A mod1f1ed Fibonacci scheme was used to
`escalate the daily oral dose; the following dosages and cycles (defined as
`treatment during 28 days) were applied, respectively 25mg 6, 50mg: 2;
`100mg 5; 200mg: 7, 150mg: 3 Over a 10 months accrual phase, 11 pts
`(7 females, 4 males) with a median age of 63 years (50-73), WHO PS 0:5,
`1 6 and miscellaneous solid tumors were entered The number of cycles
`applied per pt was median 1 5 (0-7) Reversible, dose-dependent increase
`of liver enzymes (maximal CTC grades: GGT: 4, SGOT: 3, SGPT: 3, aP: 3,
`bilirubin: 3) prevented regularly from further dose escalation. Oral med1cat1on
`yielded plasma levels far below expected to be efficacious. Realistically, target
`plasma levels could not be reached via the oral route at reasonable dosage
`Meanwhile, a preclinically unknown metabolite was 1dentif1ed from unne of one
`patient. Subsequently, this metabolite was found to be abundant in patient
`plasma The metabolite was demonstrated to be pharmacologically inactive.
`Due to dose limiting increase of liver enzymes, low bioava1fability of BIBX
`1382 and detection of a pharmacologically inactive metabolite this tnal was
`discontinued
`
`I 609PD I A phase I and pharmacologic trial of weekly
`
`epothilone B in patients with advanced
`malignancies.
`, Malcolm Moore 1
`Amit Oza 1, RM Zamek 3 , Lillian Siu 1 , SM Locsin 3
`,
`F. Chen 2 , T -L. Chen 2 , Patricia Cohen 2 , John Rothermel 2 , Eric Rubm 3 •
`1 Medical Oncology and Hematology, Pnncess Margaret Hospital, Toronto,
`Canada; 2 Novartis, New Jersey, USA, 3 RWJ-UMDNJ, The Cancer lnsfltute of
`New Jersey, New Brunswick, USA
`
`Epothilone B (EB) is a naturally occurring macrollde that 1s a more potent
`microtubule stabilizer than paclitaxel and exh1b1ts a broad range of preclinical
`anti-tumor activity at pg/ml levels. EB is also active in paclitaxel-res1stant
`models. A phase I dose-escalating trial of weekly intravenous administration
`of EB was undertaken to determine tox1c1ties, to identify a maximum-tolerated
`dose, and to assess pharmacokinet1cs Patients receive weekly infusions of
`EB every 6 out of 9 weeks and are enrolled in cohorts of 3 or more using
`a Fibonacci-based dose escalation strategy. 24 patients have been enrolled
`to date at doses ranging from 0.3mg/m2 to 1.85mg/m2 . Only one patient has
`developed grade 3 toxicity with parasthes1a to date at dose level 2 (0 5mglm2 )
`Pharmacok1net1c results are presented.
`
`Dose
`mglm2
`03
`03
`0.5
`0.5
`0.75
`075
`11
`11
`
`Week
`
`1
`6
`1
`6
`1
`6
`1
`6
`
`AUC1NF
`ng h/ml
`28
`187
`85
`312
`189
`153
`204
`NA
`
`Cmax
`mg/ml
`15
`14
`14
`28
`18
`19
`23
`NA
`
`CL
`mg/min
`462
`
`254
`
`189
`
`185
`
`Vss
`L
`1201
`
`1179
`
`820
`
`843
`
`T112
`H
`64
`73
`83
`103
`58
`63
`59
`NA
`
`At the initial dose level, drug accumulation was observed with an accumu-
`lation ratio (AUCo-SOh dose 6/AUCo-soh - · 1) of 2.45. Continued dose escalation
`is planned.
`
`protease inhibitor. Trastuzumab (Herceptin '" ), a humanized antibody against
`HER2 ectodomain, at doses of 10-100 nM, also inhibited basal and induced
`HER2 cleavage. This inhibitory effect is specific of trastuzumab, since 2C4,
`another antibody against HER2 ECO, did not show any significant effect on
`constitutive receptor shedding. The inhibition of HER2 cleavage is not due to
`antibody-induced receptor downmodulat1on, given that trastuzumab inhibited
`HER2 cleavage at 30 mm, and receptor downmodulation was not detected until
`24 h In addition, trastuzumab effectively prevented HER2 shedding in cells
`where receptor internalization was inhibited by hypertonic treatment Finally,
`an increase in the phosphotyrosine content of full-length HER2 was associ(cid:173)
`ated with APMA-induced cleavage m BT-474 cells, and this increase was less
`pronounced if trastuzumab was present. These data indicate that trastuzumab
`has a direct inhibitory effect on HER2 shedding that could contribute to its
`therapeutic properties.
`
`I 6060 I A phase I and pharmacological study of CCl-779, a
`rapamycin ester cell cycle inhibitor.
`Manuel Hidalgo 1·2 , Enc Rowinsky 1·2 , Charles Erlichman 3 ,
`2
`Ronald Drengler 1·
`, Bonnie Marshall 4 , Randy Marks 3 , Tam Edwards 1·2 ,
`Joseph Boni 4 , Gary Dukart•, Jan Buckner 3 1 University of Texas Health
`Science Center at San Antonio, San Antonio, TX, USA; 2 Institute for Drug
`Development, San Antonio, TX, USA, 3 Mayo Clinic, Rochester, MN, USA;
`4 Wyeth-Ayerts Research, Radnor. PA, USA
`
`CCl-779 is an ester of rapamycm which 1nhib1ts the cell cycle. The agent
`inh1b1ts the activity of mTOR (mammalian target of rapamycin) and disrupts
`key signal transduction pathways, including those regulated by the p70s6
`and PHAS-1 kinases resulting in cell cycle arrest at the G1-S boundary This
`study is evaluating the feasibility, pharmacok1netics and biological effects of
`escalating doses of CCl-779 administered as a 30-minute IV infusion daily
`x 5 every 2 weeks to patients (pis) with solid neoplasms Fifty-one pts
`have received 262 courses (median 4, range 1-16) at doses ranging from
`O 75-19.1 mg/m2/d. Three episodes of DLT have been observed in the 1st
`cycle so far consisting of asymptomatic, grade 3 hypocalcem1a at the 2. 1 6
`mg/m2/d dose level (1 pt), grade 3 elevation in transaminases (1 pt), and
`grade 3 vomiting, grade 2 diarrhea and grade 2 asthenia (1 pt) at the 19.1
`mg/m2/d Grade 3 thrombocytopenia requmng dose reduction was observed
`in 3 heavily-pretreated (HP) pis at the 19.1 mg/m2/d dose level, indicating that
`this dose 1s not well-tolerated in HP subjects At this juncture, HP patients
`are rece1v1ng 15 mg/m2 , while doses continue to be escalated in m1nimally(cid:173)
`pretreated pts. Other tox1cit1es noted, generally mild-moderate, some over a
`broad dose range, include neutropenia, rash, mucos1t1s, asthenia, lever, and
`hypertriglycendem1a. Allergic phenomena have also being observed. In 1 7
`pis receiving doses of 0.75-3 12 mg/m2 /d, CCl-779 exh1b1ted increasing peak
`concentrations with increasing dose, preferential red blood cell part1t1oning, and
`a median terminal hall-life of 15.2 h One patient with NSCLC achieved a PR
`Minor antitumor responses and/or prolonged(> 4 monlhs) stable disease have
`been noted in several drug-refractory cancers including: soft-tissue sarcoma
`(3), and cervical (1), uterine (1), and renal cell (3) carcinomas. CCl-779 dose
`escalation-expansion continues. The toxicity profile and antitumor activity
`observed to date are encouraging.
`
`I 6070 I Phase I study of the gene therapy prodrug, CB1954.
`
`Guy Chung-Faye, Joanna Clark, Rachael Barton, Joanna Baddeley,
`David Anderson, Leonard Seymour, David Ferry, David Kerr Institute of
`Cancer Studies, Blfmmgham, United Kingdom
`
`CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide), a substrate for the bacterial
`enzyme nitroreductase, is converted into a potent bifunct1onal alkylating agent.
`CB1954 1s a candidate prodrug in virus-directed, enzyme prodrug therapy
`(VDEPT) protocols. CB1954 was administered by bolus intravenous (IV)
`injection on a 3-weekly cycle, or intraperitoneally (IP) followed by 3-weekly IV
`injections, with a maximum of six cycles of drug. 30 patients were treated,
`age range (23-78 years, median 62 years). 19 patients were males. 22
`patients received IV CB1954, 8 patients had IP CB1954, 4 of whom also
`received IV drug. 13 cases were colorectal cancers, 4 gastric, 3 oesophageal,
`3 mesotheliomas, with ovarian, pancreatic and unknown primaries accounting
`for the remainder The first dose level was 3mg/m2, no significant tox1c1ty
`was seen until the fifth dose level of 24mg/m2. The maximum tolerated dose
`IV was 37.5mg/m2 with gastro-intestinal and hepatic dose-limiting toxicities
`(DLn. No DLT has been seen in the IP regime at the current dose of 24mg/m2.
`No alopecia, marrow suppression or nephrotoxic1ty was observed No clinical
`response was seen. CB1954 pharmacokinetics indicated a linear relationship
`between dose and area under the curve for the IV dose range of 3-24mg/m2 ,
`with a non-linear effect at higher doses. Mean elimination hall-life was 1 7
`minutes with <5% renal excretion. Animal data suggests biliary excretion
`as the main clearance mechanism. Serum levels after IV administration
`(30mg/m2), persisted between 10 and 1µM for 2 hours. IP administration
`(24mg/m2) achieved peritoneal levels between 100 and 1µM for 18 hours
`The IC50 for CB1954 in cancer cells expressing nitroreductase ranges from
`0.1and10 µM. In summary, CB19541s a well-tolerated prodrug and sufficient
`serum/peritoneal levels are generated for a VDEPT approach to be feasible.
`
`Annals of Oncology, Supplemenl 4 10 Volume 11, 2000
`
`© 2000 Kluwer Academic Publishers, Primed in The Ncihcrlands
`
`133
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`West-Ward Exhibit 1080
`Hidalgo ESMO 2000 - Page 002
`
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