ABSTRACTS
`
`.23rd Congress of the
`European Society for Medical Oncology
`
`November 6-10, 1998 -- Athens, Greece
`
`Introdfiction
`
`23rd ESMO Congress - Organisation
`
`ESMO Committees
`
`Acknowledgements
`Sponsors and Exhibitors
`
`Abstracts
`
`H~nilton Faidey Award for Clinical Research
`Invited abstract 1
`
`Pntsidential Symposium
`Abstracts 2--4
`
`Bio-iWedicnl
`Library
`
`ESMO Special Symposium "Cancer trials tmvards the millennium’"
`Invited abstracts 5-7"
`
`ESMO Special Symposium "Difficult areas in lymphoma"
`/nvited abstracts.8-.12
`
`ESMO/ASCO Joint Symposium "Controversies in ta’~atment of non-small cell lung cancer’"
`Invited abstracts 13-17
`
`Breast cancer, early
`Abstracts 18--53
`
`Breast cancer, advanced
`Abstmem 54-146
`
`Cancer in the elderly
`Abstracts 149-154
`Colomctal cancer
`Abstraet~ 155--215
`
`Gastrointestinal tum0urs
`Abstracts 217-265
`Genlt~rudnary tumonrs
`Abstracts 266-310
`Gynae~01ogieal cancer
`Abe, tracts 312-353
`Head ~d neck cancer
`Abstracts 354--381
`
`Leukaemia and myeloma
`Abstracts 382-398
`
`4
`
`I l
`
`31
`
`32 °
`
`46
`
`56
`
`65
`
`74 -
`
`79
`
`Lung (Oral presentations NSCLC + SCLC)
`Absmacts 3.99-406
`Lung, NSCLC
`Absu’acts 407.-496
`
`Lung, scLc " ¯
`AbsWact~ 497-513
`Lymphoma
`Abstracts 514-551
`
`Melanoma and sarcoma
`Abstracts 552-576
`Moiecular ontology
`Abstracts 577.-600
`Novel therapeutics and phannacoIosy
`Abstracts 601-669
`
`Palliative and supportive care
`Absu~c~s 674-724
`
`Index of authors
`Index ofsubjects
`
`’
`
`"
`
`Volume 9~ 199~
`" Supp.!ement 4
`CODE
`ISSN 0923-7534 "
`
`v
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`vi
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`vii
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`viii
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`xi
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`1
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`I
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`I
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`2
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`3
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`83
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`85
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`103
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`107
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`115
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`120
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`125
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`140 ..~-"i"~":’I :" :: .:. ::~"’"
`...-1-~:..": : :ii .-": ..........
`~-",~’: :, 169 ......
`
`Sandoz Inc.
`Exhibit 1006-0001
`
`JOINT 1006-0001
`
`

`
`de
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`thl
`pr,
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`fr~
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`Novel therapeutics and phamracology
`
`Conclusions: A rapid, sensitive and reliable methbd has been developed for
`the measurement of plasma dUrd in paflents receiving antifolate drugs. These
`data suggest that the duration of TS inhibilJon is dose-ralated and will help in the
`choice of dose and schedule for Phase II tdals of ZD9331 and understanding
`the relationship of duration of target inhibition and response/toxicity.
`
`~
`
`for improvement in dose.escalation using
`Strategies
`the continual reassessment method (CRM) in phase I
`clinical trials
`
`LL Siu, X. Pacletti, J. O’Quigley, E.K. Rowinsky, G.M. Clark,’D.D. Von Heft,
`S.G. Eckhardt. Cance~ Therap.v and Research ~enter’ San Antonio, TX, USA
`and U436 INSERM, Pads, France
`
`The CRM has been proposed as an alternative dos.e escalation method in
`the phase I clinical tdal 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 ulilized is a sequential Bayesian’
`estimation scheme in which a prior disbibution function of th~ maximum
`tolerated dose (MTD) and a dose toxic-response modal are selected before
`the tdal. The MTD is the dose at which a pro-determined percentage (e.g.
`30%) of the pt population would experience dose-limiting toxicity (DLT, e.g. Gr
`3 non-hematologic orGr4 hematologic). In response to the practical and safely
`concerns of cytotexic chemotherapy, modifications 6f the CRM (MCRM) were
`implemented which include the use of a conventional .sta~ng dose and the
`fixation of dose levels a prod, c.ustomadly 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
`pdo? to the tdal, and the difficulty of predicting a fixed number Of dose levels.
`Therefore, we have di~signed a "dual-stage" escalation scheme. The initial
`stage involves utilization of a conventional ste~ng dose will] 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 Shah)
`is applied which offers greater flexibility without restriclion by the paucity of
`pdor data. Practical examples and simulations of models will be provided to
`illustrate this proposed dose escalation method.
`
`~ Synergistic antitumor effect by novel modified
`oligonucleotides targeting PKAI combined with
`cytotoxic drugs or monoclonal antibodies
`
`G. Torero, V. Damiano, R. Btanco, S. Papa, A.R. Bianco, S. Agrawal~,
`J. Mendelsohn2, F. Ciardiello. Oncologia Medico, Univ.Fededso II, Napoli,
`Italy; ~ Hybridon, Cambridge, MA, USA; ~ U~-MD Anderson Cancer Center,
`Houston, TX, USA
`
`Introduction: Protein kinase A type I (PKAI) plays a key role in neoplastic
`transformation and conveys mitegenic signals of dfferent growth factors and
`oncogenes. Moreover, PKAI is overexpressed in cancer cells with an active
`TGFc~.-epidermal growth factor receptor (EGFR) autocdna path~vay and shows
`a structural and functional Interaction with EGFR. Inhibition of PKAI, or its
`regulatory subunlt Rhz, results in cancer growth inhibition in vitro and in rive.
`Methods: A novel dasa of mixed backbone oligonuclestides (MBOs) tar-
`geting PKAI (ASRI~}, with improved pharmacaldnefic and bioavailability, and a
`human!zed monoclonal antibody which blocks activation of EGFR, MAb C225,
`Iiave been tested in vitro and in rive on several human cancer cells.
`Results: A dose-dependent inhibition of soft agar growth was obtained in
`all cancer types tested with the AS Rhz MBOs, as compared to mismatched
`control oligos. Non-inhibitory doses of each MBO resulted in .a synergistic
`growth inhibition and in0reased apoptosis, when combined with taxanes,
`platinum-derivatives and tope g-selective drugs. When the MBOa sdministered
`either i.p. or p.o. were added to paclitaxel, a cooperative effa¢l was also
`obtained in vivo, causing tumor growth inhibition and increase of survival in
`nude mice beadng human cancer xenografts. Finally, combined treatment of
`human breast and renal cancer cells, which overaxpress PKAI and EGFR,
`with the ASRIu MBO and MAb C225, caused a (cid:128)odperative anfitumor effect in
`vitro and in rive.
`Conclusions: Since both the AS Riot MBOs and the MAb C225 are currently
`studied in clinical trials, the combination between them or with selected
`cytotoxic d~gs may represent a feasible novel therapeutic strategy.
`
`~-~’~ Ph~rmacokinetic (PI0 interaction of the, combination
`of d;oxorubicin (DOX) and Taxotere (]XT),
`J. Sch011er, M. Czejka, E. Kraxner, K. Lehner, H. Bucher, .G. Schamthaner.
`Hospital Rudolfs.tiftung OncoL Dep., Instil pharma chain Vienna, Austria
`
`Introduction: Combination of DOX with TXT has been shown to be highly
`effective in advanced breast cancer recently introduced into ediuvant treatment.
`Purpose of the present study was to detect a potential PK interaction between .
`
`DOX and TXT, as already proven for Paclitaxel + DOX leading to increased
`DOX-AUC and enhanced cardiotoxicity (Gianni et at). Therefore PK behavior
`ef both, DOX and TXT, was analyzed using 2 different time schedules: DOX
`50mg/m~ 30min inf. followed immediately (A) of after 1HR intewat (B) by "P/r
`75mg/m~ 1HR infusion.
`Methods: All pt~ received TXT alone at cycle 1 for baseline determination
`followed by DOX + TXT (18 pts schedule A, 13 pts B, sampling for beth DOX
`and 1XT), followed by DOX baseline analysis (12 pts A, 6 pts B, TXT then
`given delayed after end of DOX sampling). Sampling pedod 4HR for TXT and
`6HR for DOX, measured by HPLC, Win Nonlin noncompartimental analysis
`performed.
`Results: of the respective AUG last:
`
`AUC
`ngfmI.H
`
`A
`B
`
`Tax~)tere
`
`n
`
`18
`13
`
`TXT
`
`1484
`1703
`
`DOX/’PAT
`
`!956
`2450
`
`p
`0.03
`0.05
`
`n
`
`12
`6
`
`Doxorubic!n
`DOX
`DOX/TXT
`
`859"
`906
`
`848
`833
`
`p__
`
`0.9
`0.6
`
`Conclusion; NO influence ef TXT on DOX-AUC decumented, DOX-ol cans
`(n=8) with or without TXT n.s. different {p 0.2 - 0.8)~ :thus explaining low
`cardiatoxicity at the ~0mbinatian. In contrast, TXT-AUC was significantly in-
`creased when combined with DOX, suggesting interference at the hepatic
`microsomal level, partly explaining high clinical efficacy. A 1 HR delay between
`end of DOX and start of TXT does not change the respective PK behaviour of
`both drugs.
`
`~"~7 Gemcitabine (GEM) - cisplatin (CDDP): A schedule
`finding phase 1/11 study
`
`J.R. Kroep~, G.J. Peters~, C.J.A. Van MoorseP, J.B. Vermorkan~,
`P.E. Postmasa. A. Catik_~, _H.M. Pinedo~_,.C.J. Van Groeningenf. ~DepL Oncal.
`and ~ Pulm., Univ. Hosp. VU, Amsterdam, NL and aDept, Oncol., Univ. Heap.
`Antwerp, B, The Netherlands
`
`Introduction: Gem and CDDP are active against various solid tumors. Since
`preclinical studies demonstrated the efficacy of vadous schedules we evaluated
`the tolerability and clinical efficacy of 4 different Gem/CDDP schedules as part
`of a pharmacoldnetic and -dynamic (PWPD) study.
`Methods: Gem 80D mg/m~ was adminiate~:ed as a 80 min infusion on d 1, 8,
`15, and CDDP 50 rag/m~ over 1 hr on d 1, 8 every 28 days; Gem 4 hr before
`CDDP (10 pts), 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
`ovadan, 7 non-small cell lung (NSCLC), 5 head/neck squamous cell (HNSGG),
`5 esophageal, 4 melanoma, 4 cervix, 3 adenocarcinoma, 2 pancreatic, 2 colon
`and 1 small cell lung (SOLO). 26 pts received prior chemotherapy, of which 21
`platinum based.
`Results: A mean of 4.2,..2.6, 3.8 a~3~l 3.5 cycles was given in the four
`schedules, resp. The most frequent overall grade 314- CTC-toxicity was throm-
`bccytopenia, 6/10, 4/14, 2/9 and 6/9 (overall 60%), followedby leukopenia,
`8/10, 5/14, 619 and 6/9 (4,3%}, in the 4 schedules, resp. Therefore, Gem was
`not given on d 15 in 36°/, of pts in cycle 1. Anemia was observed in 64%
`of pts. No serious bleeding occurred. Myelotoxicity was cumulative, but not
`schedule dependenL Non-hematological toxic~ consisted mainly of grade 1/2
`nausea!vomiting and fatigue,.One patient died of toxicity following severe neu-
`tropenia and sepsis. Creatinine clearance desreased slightly during therapy.
`Anti-tumor effects
`in 36 evaluable pts: HNSCC, 1 OR; esophageal, 1 CR/2PR;
`ovadan, 2 PR; NSCLC, 1 PR; melanoma, 1 PR and adanocarcinoma, 1 PR.
`Conclusion: (Cumulative) myalosuppression was the major 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 pte with
`upper gastro-intestinal tumors.
`
`~-~MTA (LY231514): Relationship of vitamin metabolite
`profile, drug exposure, and other patient
`characteristics to toxicity
`C. Nivikiza. S. Baker, R. Johnson, J. Walling, D. Setiz, R. Allen. UIIyResearch
`Laboratories, Indiana, USA; Cancer Treatment and Research Center, ~exes,
`USA; Unfv of Colorado Health Sciences Center, Colorado, USA
`Introduction: M’I’A is a novel multitargeted antifolate with inhibitory activity
`against multiple enzymes. Phase 1/11 studies have shown activity In a vadety
`of tumors. Historical data on other antifolatos have suggested thai a patient’s
`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 melabolitas,
`drug exposure, and otherpraspecified baseline patientcharactadstics totoxicity
`following treatment with MTA.
`Methods: Homocysteine (Hays), eystathionine and methylmalonic acid were
`measured in 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 discdminant analysis
`were implemented to determine which predictors might correlate with severe
`toxicity after one course of MTA. Prognostic factors considered were age, gen-
`
`126
`
`Annals efOncolo~,, Supplement 4 to Volume 9, 1998 © 1998 Kluwer AcademlcPublishers, Printed ha The H=therlands
`
`Sandoz Inc.
`Exhibit 1006-0002
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`JOINT 1006-0002
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`
`der, pdor tre~atment, baseline albumin, liver enzymes, ANC, platelets, vitamin
`metaboliles,’and AUG.
`Results: Statistically significant predictors of Grade 4 neutropenia (n=21
`pts) were albumin (p = 0.0006) and Hcys (p = 0.0012), while Grade 4
`thrembocytopenia {n=8) was highly predicted by Hcys (p < 0.0001) and
`pro-treatment AST (p = 0.0012). Hcys >_ 10#M predicted Grade 4 neutmpenia
`In cycle one. 75% of the time. Grade 4 neutropenia was predicted by Hcys
`alone in 70% of cases. Hcys and albumin levels did not appear to change
`from baseline dudng ti’eatment with MTA. While AUG was not found to be a
`predictor of toxicity, It[tie variability was obsen~ed in AUG. Maximum values
`were still below AUG values related to hematologic toxicity in phase I studies.
`Conclusions: Toxicities resulting from treatment with MTA appear to be
`predictable from pretreatment hemecysteine levels. Elevated baseline ho-
`mocysteine levels (>_ 10/~M) highly correlate with severe hematologic and
`nonhematoiogic toxicitias following treatment with MTA. Hdmecysteine was
`found to be better than albumin at predicting toxicity. These results apply to
`ths tumor types sthdied. Further studies are underway in patients with renal
`impairment or patients who received pdor cisplatin.
`
`Phase I and pharmacokinetic (PK) study of Tomudex
`(TOM) + 5-Fluoroura¢il (5-FU) and levofolinio acid (LFA)
`in advanced head and neck and colorectal cancer
`
`F. Caponiqro, R. Casaretti, H.L. McLeodr , A. Buditlon, G. Cartani, F. De Vita,
`A. Avallane, M. Biglialto, A. Tucci, J. Momman1, D. Barbamlo, G. Catatsno,
`P. Comella, G. Cornelia. Southern Italy Cooperative Oncology Group c/o
`NationM Tumor Institute of Naples, ITALY," r Univemi~y of Aberdeen, UK
`Background: Synergism between TOM and 5-FU + LFA~s obaewsd in vitro
`when ceils are exposed for 24 houm to TOM, followed by 5-FU + LFA.
`Predinical studies support the idea thatTOM might down-regulate the activity
`of dihydrepyrlmidine dehydrogenase (DPD).
`Patients and methods: Patients (pts) with advanced head and neck and
`cctorectal 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 pretreatmant with TOM.
`Furthe[ treatment was given according to the sequence used.in the 1 course.
`Results: Availebte clinical data are summatiTed below.
`
`Type"
`
`Response
`
`Step ~OM/LFN5FU (mg/rn2) Pts C/HN" DLT
`1.5/250/600
`6
`t/5
`2.0/2501600
`5/1
`6
`5/1
`2.012SO/ZSO
`6
`2.5/250/750
`6
`5/1
`" 2.512501900
`7
`6/1
`3.0/250/900
`8J0
`8
`3.0/25011050
`9/7
`le
`2/1
`3,01250112Q0
`3
`58
`41/17
`
`t
`2
`3
`4-
`5
`6
`7
`B
`Total
`
`0!6
`0/’6
`0/6
`0/6
`0/7
`N 4
`1/8
`3/15 N 4; N 4; N ~1
`2/3 N4, M3;R3
`
`3/6 (2CR, 1PR)
`0/7
`1/’8 (CR)
`6/13 (1CR, 5PR)
`1/3 (PR)
`OR
`
`"C = colorectal cancer;, HN=head & neck cancer. C = 6/39 (15%); HN = 7/16 (44%); ° N =
`neubopenia; M = mucositis; R = Renal
`
`DPD activity has been measured in 14 pts thus far. Pretherepy DPD activity
`was a median 34% higher than after TOM administration (95% C.l. -93 to
`+62%). PK data are available in 6 patients thus far, and 5-FU AUG basal
`values do not significantly differ from values obtained 24 hours after TOM.
`Conclusions: The combination of TOM+ 5-FU/LFA is well tolerated every
`2 weeks. Clinical activity looks very encouraging, since the majority of pts had
`already received prior chemotherapy. We are now treating some additional
`chemo-nalve patients at step 7, in order to have a more reliable estimate of
`the activity of the regimen.
`
`r~-~ Radio-localization of pulmonary nodules using
`gamma-probe and resection by video-assisted
`thoracic surgery
`
`A. Challa~ G.F. Menconi, F.M.G. Mold, A. Gonffotti, G. Bent1, G. Gresso1,
`E. Baldini2, C.A. AngeletiL Sen4ce of Thoracic Surge~ Department of
`Surge~, ~ Service of Nuclear Medicine and ~ Service of Medical Oncdiogg
`Department of Oncalogy, University of Plea, Italy
`
`Video-assisted thoracic surgery (VATS) is emerging as safe procedure for
`diagnosis and treatment of peripheral pulmonary nodules. One limilatlon of
`thoracasco.pic 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 pdor to
`excision, including methylene blue injection and introduction of hooked-wire;
`however, all suffer from limitations. Recent advancements in intraoperative
`radio-localization of non-palpable breast lesions prompt us to develop a new
`tashnique for detection of pulmonary nodules by VATS. CT-scan are used
`to guide pedlesionat injection of 0.2 - 0.5 ml of solution of 99m To-labeled
`human serum albumin micmspheres (5--10 MBq) and 0.2 ml of Iodine-non-ionic
`conti’as! medium, two hours before surgery. In VATS a gamma ray detector
`(Scinti Probe MR 100 - PoLhi.tech., Aquila, Italy), equipped with 11ram
`
`Novel therapeutics and phannacology
`
`diameter-collimated probe, allowed us to locate that lesion for thoracoscopic
`resection. From June lg97 to January 1998 we treated 15 consecutive patients
`(pts) with sub-centimeter pulmonary nedutss. Nine pts were affected by a
`synchronous and metachranoua 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 radieastivity 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 9verege
`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 pleura! surface projestlon and fast
`removal of the lesion. This technique offers a simple and reliable msthdd for
`Incalizatien of primary and metastatic tumors by VATS.
`
`r~--~ Pharn~acokinetic (PI0 of Tomudex® (raltitrex~d) (T)
`and oxaliplatin (0) combination: Preliminary results of
`an ongoing p.hase I study
`
`K. FizazP, M. Boanay~, D. Fourcaultr, P. Ruffidr, O. Coutures2, M. Smith2,
`R. Gomeni~, A. Fandi2, J.P. Armand~. ~lnstitut Gustave Roussy, Villejuif,
`a Zeneca Pharmaceuticals,. Cergy, France
`
`Introduction: The aim of this study was to evaluate the possible kinetic
`interactions between T and O administered to patients with advanced disease.
`Methods: Patients first received T (15 rain infusion), followed 45 minutes
`later .by O (2-hour infusion). Three patients received T at a dose of 3 mg/m~
`and 3 at a dose of 3.5 mg/m~. All of them received the same dose of 130
`mg/m~ of 0 ........ - -"
`Results: Plasma concentrations of T declined t-i-exponentially after the
`end of the infusion. The terminal tl/2 derived from samples up to 28 hours
`post-dose vaded between individuals from 9.3 to 193.2 h with average values
`of 7:3.4 and 33.7 for the two dose levels. The maximal concentrations vad~d
`between 323 and 1185 ng/ml with averages of 681 and 813 in the 3 mg/rn~ and
`3.5 mg/m~ groups respectively. The AUG varied between 720 and 3192 ng.ldml
`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 m. ean AUG 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 tl/2
`vaded from 18 to 30 h (average ~f 25). Cmax ranged from 3.13 to 4.53 (average
`of 3.69)/~g/ml. The AUC ranged from 74 to 120 (average of 195) #.g.Wml and
`the CI varied between 1.76 and 3.43 (average of 2.47) 1/h. The comparison
`of the kinetic parameters of O to the ones previously published in the same
`experimental conditions s~e-rfi-s to indicate that T induced an increase of O CI
`(from 1.32 to 2.47 l/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/~g/ml.
`Conclusions; These preliminary results suggest that the expected concen-
`trations of O obtained after administration of T may be lower that the ones
`obsen/ed when O is administered alone. These results indicate possible PK
`inlerection between the two drugs.
`
`~3--P7 A phase I and pharmacoldnetic (PI0 study of ET-743, a
`novel minor groove binder of marine origin
`administered on a daily × 5 schedule
`
`M. Hidalqo, M.A. Villalona-Calero, S.C. Eckhardt, G. Weiss, E. Campbell,
`M. Kraynak, J. Beijnen, J. dimeno, D. Yon Heft, E. Rowinsky. Cancer Therapy
`and Research Center, San Antonio, TX, The Netherlands Cancer IOstitute,
`Amsterdam, The Netherlands; PharmaMar, S.A., Madrid, Spain
`
`ET-743 is a novel tetrahydrotsoquinoline, alkaloid isolated from the madne
`organism Esten~iasidian 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 × 5 every 3
`weeks in patients with advanced solid malignancies. Twenty-seven patients
`(median age 58, range 35-79; median ECOG PS-f) have received 67 courses
`of ET-743 at doses ranging from 6 to 380 #.g/m~/day. At the 380/zg/m~day
`dose level, 1 patient with extensive prior Ireatmant with 16 cycles of BCNU
`developed grade 4 thrembasytopenia, grade 4 neutropania with fever, grade
`3 elevation in trensaminases, and acute renal failure which resulted in death.
`Four patients (8 cycles), at the 216 (1), 287 (1) and 380 (2) p.g/mS/day dose
`level developed asymptomatic elevation in hepatic transaminaess of grade
`:3 severity that typically peaked on day 6 and resolved by day 21. Mild to
`moderate, desedependent nausea and vomiting, which appeared on day 4
`and resolved on day 8, was observed in 14 patients. Two patients at the 380
`,ug/mZ/day dose level suffered supedicial venous thmmbophlebitis at the drug
`infusion site. PK parameters obtained in 2 patients at the 218/zg/m2day dose
`level included: clearance, 137 and 589 mL/min/m2; trra, 13.7 and 23.1 L/h; and,
`
`Annals of Otzcology, Supplement 4 to Volume 9,1998 © 1998 Kluwer Academic Publishers, Printed in The Netherlands
`
`127
`
`Sandoz Inc.
`Exhibit 1006-0003
`
`JOINT 1006-0003