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`An Official Journal
`of the
`American Association
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`Cancer Research
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`3 EuropeanOnsanization forResearch
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`OSI 2025
`APOTEXYOnt
`|November 1999 * Volume 5 © Supplement
`APOTEX V. OSI
`IPR2016-01284
`|PP. 3729s-3897s ° ISSN 1078-0432
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`An Official Journal
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`Molecular Targets and
`Cancer Therapeutics
`Discovery, Development,
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` 1999 AACR-NCI-EORTC International Conference on
`
`Abstracts are numbered from 1 through 695;
`however, several numbers may be omitted in the
`sequence. Abstracts were either typeset or repro-
`ducedelectronically from submitted material. Every
`effort has been made to reproduce the content of
`the abstracts according tothe paper copy submitted, —
`except, in certain instances where changes were
`made to comply with AACR style. AACR does not
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`and copyright owner of the Proceedings ot by the
`meeting organizers for any injury and/or damage to
`persons or property as a matter of productsliability,
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`contained in the material herein. Independenit
`verification of diagnoses and drug dosagesshould
`bemade by readers or users ofthis information.
`
`'
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`The Proceedings ofthe AACR-NCLEORTC intentational- Conference onMolecular,
`Targets and.Cancer Therapeutics \s printed for the AACR by Cadmus Journal:
`Services, Lmthicum, MD 21090-2908 andis distributed to registrants and
`~~ other attendees of the 1999 AACR-NCI-EORTC International Conference.
`In addition, the Proceedings is stmultaneously published as a Supplement
`‘to Volume 5 of the AACR journal Clinical Cancer Research (Novernber.
`1999; ISSN: 1078-0432). The Proceedings may be obtained.ata price of
`$25.00 by writlng to: AACR Subscriplion Office, P.O. Box 11806,.
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`rights reserved. Redistribution otresale of the Proceedings or of any materials
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`form, Is prohibited. Reproduction for-advertising or promotional purposes, -
`by reproduction In any form, may be permitted only under license from
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`Addiess inquizles to the Office of the American Associationfor Cancer\
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`
`.
`
`~ MolecularTargets and—
`Cancer Therapeutics
`
`Discovery, Development, and Clinical Validation
`November 16-19, 1999 « Washington, DC
`
`.
`
`‘
`
`April 6-10, 2002 ¢ San. Francisco, CA
`
`FUTURE ANNUAL MEETINGSOF THE AACR
`April 1-5, 2000 « San Francisco, CA
`March 24-28, 2001 * New Orleans, LA
`
`9
`
`

`

`Table of Confents
`
`.
`
`:
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`Clinical Cancer Research * Volume 5 * November 1999 (Supplement)
`.
`
`Program Committee and Special Committee for Review of Abstracts...ceecseesneeaerseetsyesstenstacsensere esVi
`
`Regular Abstracts: Poster Sessions
`Poster Session1 . "eprintTOS
`Section1: Phase IClinical Trials:“New Agents, Antiangiogenesis, and Moleciilar Bridpoints...
`| wserseeedF298
`Section 2: Growth Factors and Theit Responses (Including Antihormonal).wadenessrseerrrsnedenesstpesensanneesstage3734s
`Section 3: Metastasis and Invasion Targets ......sss.cccseneeeeepeebenpescecasenienestansseveressaeeneeesdeeeseseessettee7395
`Section 4: Fas Pathways/Growth Factors: Biology and Therapeutics denensessecesecessuanssnseqarssnsannecesieesen137445
`Section 5:Kinase INHiDItOLS.o.cccscleseesselesceserettrescecssensecscsssennyseeeentacdventensseossuseessesssnnssctsananecteuettedbonsseveeaeee 37495
`
`Section 1: Cell Cycle Targets: p53, Cyclins, Cyclin-dependent KUDASCS0. .sseeesstsecbessesetnssesnnseerisenceed7548
`Section 2: Cellular Therapy, Vaccines, and ImmunologicTargets sclesessseeseZlasessustunsestsseresssssseeestvessasseeee3758S
`Section 3: New Intracellular Targets ........-.s:00ececonneesandeeeeseneeeseeseneednnvcenneennisesanesvapeceeteteneeseseavesnny3763s
`Section 4: Tumor Physiology: Hypoxia, Radiosensitization, and New Extracellular Targets ..c.tesssss37685
`Section 5: Phase II Studies with Molecular Endpoint ...csccssssccccccsessessesssscerstseteerrrecersenedeseeessnanssssnsnasse37725
`
`..cccsccssesseesssssseserererspentiessesenenenessssesdedsecteaeaeee centeesleneecnseen seaeecapnaecenseeuestensasanreescarensned 2 708
`Poster Session 3.
`Section 1: Genomics and High Throughput Screens For Target Discovery .
`(Arrays and Chips)/Signal Transduction (Related to Gene Expression).......caccaeneeneaaaeLaneennsesneecereeetenenys3776s
`Section 2: Structure-based Drug Design/Agents with Unknown or Uncertain Targets vevsslecesveseeneneees3780s
`Section 3: New Agents.....,...-.-s0+vase caneeaceeesecuneneseeqeatanentarenTeevsreteeenseseseseeees seeesenetseaeesssa decaeseseeeesastaneesensas3784s
`. Section4: Marine Compounds and Other Natural Products, Synthetic Approaches.......-cesses3789s
`Section 5: Phase I Clinical Trials: DerivativeNew Formulations, and Combinations........cc-sese1.37945
`Poster Session 4 ssantansssuasseeasissecneenennnnevectneedveeniiveceiyqesuessiusasstssetuaseeeensstnarsenatoitsssesesssenseseeBOOS
`
`Section 1: Signal Transduction/Signaling Targets sosserepeifanvisesasssesssseesuusesseseeesasennsnaeesencattaneececgeestensteras ses DBOOS
`Section 2: CYtOKIMGS -......ccseeecerersnsentreseeesneneeensNaqetseeeespeeeneecyaneeeecesneeenreeciaseesieeerteteesesssteeerssapanens‘aeDBO4S
`Section 3: Antiangiogenesis/Antivascular Targetssscscssescsesntnncintanreeieteteneeepeseenscdaeeeeeeenetacenens3808s
`Section 4:Cell Biology-based Strategies: Apoptosis anid Differentiation. wsiernadeani seasbbveeserenesanettienieneS138
`Section 5: DrugDelivery, Prodrugs, and Toxicology...........ceceeensssestetussninastsuaeieteeeneeeeeessecenesesceraeeee-38188
`
`
`
`
`
`ae
`10
`mo
`Proceedings of the 1999 AACR*NCI*EORTC International Conference
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`Lo.
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`

`Table ofContents
`.
`Clinical Cancer Research « Volume.S * November 1999 Gupplement)
`
`
`tii
`
`‘ Poster Session 5 saceeeeenaqenscuesssssanccneccconsaqaceeshesssseseeeeeeenssscenssasuseuiteceececeseceuitsiecssaausensasssssnsssssssneessessSOLES
`Section 1: Molecular Markers and Tumor Imaging: Diagnosis, Progression, and Drug Responses........38245
`Section 2: Telomerase and Gene Therapy-based Technology.....ssedansasleveseeseebessnasseevnaeteeseseeeeuseeeresesees3828s,
`Section 3: Drug Resistance/Modifiers ...... ccc ieseseereeereeenereeeenescuecesseaguentneaesnesseatsaneneasLeaeeeeeaeeeeveeneeees3832s
`Section 4: Preclinical Pharmacokinetics/Pharmacodynamics.........-e-seeseeeeeeiessvstaseieeeteereaeenens3837s
`Section 5: Drug Design, Metabolism, and Pharmacogenetics ......ssesssesresees:fv evcauneeessaeraerenanensrteeneren3841s _
`
`PosterSession6 ........seesstuetensenerseee veccgsseceeapecsasaeeeaeseneaneaees sesesueseaceesssaesteesaesvensecsens seuesaceseseeeswrens 38465
`
`Section 1: DNA-targeted Strategies: Otigodeoxynucleotide and Modulation of Repait Pathwayseseees3846s
`Section 2: DNA-interactive Agents -.......0..- scene seeneenesaceaeensnneeeeersneeeeeeatesive eeatenneceseeeecaneseneasenans3851s
`Section 3: Tubulin-interactive Agents.........seseneeceeesneebes seteteseesenseteeeaeaeersseecneecnecenensseececnsarsttsneasense10 3855S
`Section 4: Antifolates and Topoisomerase Inhibitors.......0+--secsunaseenanesvnsetusnennvnnetesessuenesinse+1.38605
`Section 5: Chemoprevention: Targets, Models, Biomarkers, and Trials ...........-0:0+seseeeseneenjesacnereaeness 3864s
`
`Invited Abstracts: Plenary Sessions............00sececececesgssteusesesssssssessnsnneeseesssuapiiisesenssevaevaneeeseeeensnaes 3869s
`Plenary Session 3: Chemistry: Generation of Diversity wreaenaeeseepeeeecanneneeanneneeasaececaesenersseedeneeeehetenecteaes3869s
`Plenary Session 4: Biology and Target Selection II sossssessessestsesnensetsneseessenraeeseeseeese?Nebeeeeestenssceteeasacetaceqe QOO9S
`_ Plenary Session S: Preclinical Development .....:ssscssssssissscssseeessnesecsecernssesceteceneesseectannetssseesssseeestanaess3869s
`Plenary Session6: Imaging Molecular Targets sevenceseteneedsceecastnnesagsevesesiesennsnsnanteassesssseeveeeee38708 _
`Plenary Session 7: New Opportunities for DNA and Microtubules fedeyaaesaceeceasseeeseessseannariaescerecireieres eeOOFES
`Plenary Session 9: Changing a Concept into a Drug: The AXt Of Patience coccicesses ese r cre rereeOZ3S
`
`"Invited:Abstracts: Workshops... snafnanaecinaniadigieniunnnnindenmangtriuenansnnnny38TSS
`Workshop 1: RelevanceofIn Vivo Models’for Target--directed Anticancer Drug Development......seerDOTOS
`Workshop 3: Cytostatic Agents: Methodolgéyof PhaseY/N Trialsiscccssceveccscesecevvcescneeersevesfeseeeevnpesnesee38768
`Workshop 6: New Cytokines anid Cell-basedTherapy)of:Cancerserteeesseesaeseesesueneceenecaeaeecenvenseasysesssateaeee3876s
`Workshop 7; Prevention Targets cissecceeeeseecacesasessvepsssenSivesibesssssssesrnsseeeeresseesensieesseseaseadeecnesenencecnseenetanscs38775
`Workshop 8: The Tumor Microenvironment sespestaeeusveseeseeaesssssesleandrdvenconsseneersvinenesseats:sevsneesseseeeneeneanae3877s
`Workshop12: Signal Transduction Targets in Cancer Drug Discovery sessesaleslessiesseeesesseverrinepeeeeernascasee38795
`
`
`
`Author Index...cossevetusanassenevenvaseseesienesasinecuaseseeesecsenuansenesstusnaseeevessyssessseneesseseeeeneeseeetvn3880s
`
`Subject Index ...... cscsSv eteeeeeetseareenneeeeesvevecebneepettenseonseqtssseascessssesuersssenseeenenscisesogeeass seseeneseaeeeseeeaees3893s
`
`Note Regarding Abstract Notation: Abstract numbersin italics denote abstracts that are published but nat presented at the meeting.
`
`11
`
`Proceedingsof the 1999 AACR*NCI*EORTCInternational Conference
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`11
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`Breit
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`reer
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`April 1-5, 2000
`
`915" ANNUAL MEETING
`
`
`Moscone Center, San Francisco, CA
`
`Chairperson: Peter A. Jones, Los Angeles, CA
`Co-Chairpersons: Carlos A..Arteaga, Nashville,TN; Franco M. Muggia, New York, NY:
`Geoffrey M. Wahl, San Diego, CA; and Alice S. Whittemore, Stanford, CA
`
`
`JANUARY 14-18, 2000
`DNARepair Defects
`_
`Chairperson: Richard D. Kolodner, La Jolla, CA
`San Diego Hilton Beach and Tennis Resort
`oo
`San Diego, CA
`
`.
`
`.
`
`.
`
`MAY3-7, 2000
`_ Melanoma: Basic Biology and
`_ Immunological Approaches to Therapy_
`Chairpersons: Meenhard Herlyn, Philadelphia, PA, and,
`Giorgio Parmiani, Milan,Italy
`The Woodlands Resort,
`—
`The Woodlands (near Houston), TX:
`
`JANUARY 26-30, 2000
`Transcription Factor Pathogenesis of
`- Cancerat the Millennium
`|
`Chairpersons: Peter K. Vogt, La Jolla, CA,-and
`‘Frank J. Rauscher,III, Philadelphia, PA
`Marriott LagunaCliffs Resort, Dana Point, CA.
`
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`AACR memberswill receive brochures onthe
`
`above conferencesas soon as they are available.
`Nonmembers should call or write:
`
`
`
`
`
`
`
`
`
`American Association for Cancer Research
`Public Ledger Building, Suite 826
`150 S. Independence Mall West
`' Philadelphia, PA 19106-3483
`215-440-9300 ¢ 215-351-9165 (FAX)
`E-Mail: meetings@aacr.org
`For regular updatesto this list visit the AACR’'s
`Website, hitp://www. aaer.org.
`
`
`
`SEPTEMBER 20-24, 2000
`Cytokines and Cancer: Regulation,
`Angiogenesis, and Clincal Applications
`Chairpersons: Janice P. Dutcher, Bronx, NY; Michael Lotze,
`Pittsburgh, PA; and Giorgio Trinchieri, Philadelphia, PA
`Vail Cascade Hotel & Club, Vail,CO
`
`4
`_NOVEMBER 12-16, 2000
`:
`+» New Targets for CancerIntervention —
`«Join Conference with theIsraeli CancerSociety
`
`-
`-*ehaipesons: Webster K. Cavenee, La Jolla, CA, and
`oe
`Pnina Fishman, Petah Tikva, Isracl
`RoyalBeach Hotel, Eliat, Israe!
`
`FEBRUARY27- MARCH 2, 2000
`Programmed Cell Death: Regulation;
`
`Basic Mechanisms, andTherapeutic
`Opportunities
`Chairpersons: John C, Reed, La Jolla, CA, and -
`Junying Yuan, Cambridge, MA
`Hyatt RegencyLake Tahoe, Incline Village, NV
`
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` |
`
`vi
`
`Committees
`Clinical Cancer Research * Volume 5 « November 1999 (Supplement)
`
`
`PROGRAM COMMITTEE
`
`Daniel D. Von Hoff, Co-Chairperson
`
`Robert E. Wittes, Co-Chairperson
`
`Jean-Claude Horiot, Co-Chairperson
`
`Shiro Akinaga ............dpowa Hakko Kogyo Co., Shizuoka, Japan
`CarmenJ. Allegra.......een NOL Bethesda, MD
`Karen S. H. Antman............Columbia Presbyterian Medical Center,
`New York, NY
`
`Susan G, ArbucR 0.0000cca dNGL Bethesda, MD
`
`Jean-Pierre Armand..........festitut Gustave Roussy, Villejuif, France
`Joseph R. Bertino..............Memorial Sloan-Kettering Cancer Center,
`New York, NY
`
`George R. P. Blackledge .......000AsiraZeneca Pharmaceuticals,
`:
`Macclesfield, UK
`
`Bruce A. Chabnet......Massachusetts General Hospital, Boston, MA
`Michaele C, Christiann ......eeceuseuee ssc CE Bethesda, MD
`Nei] J. Clendeninn......wwAgourort Pharmaceuticals, San Diega, CA
`Susan P. C. Cole o... Queen’s University, Kingston, Ontario, Canada
`
`O. Michael Colvin ................uke Comprehensive Cancer Center,
`.
`Durham, NC
`
`Esteban Cvitkovic ........Cviikovic Assoc. Consulfants, Paris, France
`
`Pieter H. M. DeMuldet «0.0....ceceecoeeseeUniversity Hospital,
`Nijmegen, The Netherlands
`Maurizio D’/Incalci...........000.Mario Negri Institute, Milan, Italy
`Robert T. Dort -....cee Arizona Cancer Center, Tucson, AZ
`
`John A. Double 20.e eee versity ofBradford, UR
`Janice P. Dutcher....Our LadyofMercy Cancer Center, New York, NY
`Alexander M. M. Eggermont..........University Hospital, Rotterdam,
`The Netherlaras
`
`
`
`Gerhard Eisenbrand.....,........University ofKaiserslautern, Germany
`Elizabeth A. Eisenhauer,................20Queen's University, Kingstan,
`Ontario, Canada
`
`LorettaItri............2. Wo Johnsen Pharmaceutical Reseatch Institute,
`Raritan, NJ
`
`Corey H. Levenson... csc dTLEX Oncology, San Antonio, TX
`Kim Allyson Margolin..........City ofHope National Medical Center,
`Duarte, CA
`Silvia Marsoni....Southern Europe New Drug Organization, Milan, Italy
`Alex Matter ...........
`veeeeeee Wovortts Pharma AG, Basel, Switzerland
`
`Frank McCormick........University of California, San Francisco, C4
`
`Jj. Patrick McGovren......Pharmacia & Upjohn, Inc., Kalamazoo, MI
`
`John Mendelsohn....................07 M.D. Anderson Cancer Center,
`Houston, TX
`ChristopherJ. Michejda ........s0NCEFCRDC, Frederick, MD
`David R. Newell ................Umiversify of Newcastle-upon-Tyne, UK
`
`Makoto Ogawa...Aichi Cancer Center, Nagoya, Japan
`Allen I, Olifé ........DuPont PharmaceuticalsCompany, Wilmington, DE
`
`Homer L. Pearce..........Lilly Research Laboratories, Indiartapolis, IN
`
`MartineJ. Piccatt..............Jnstitut Jules Bordet, Brussels, Belgium
`
`Herbert M. Pinedo ..............Free University Hospital, Aristerdam,
`The Netherlands
`
`Pat Price ..........cccne cere
`
`wo ddammernsmith Hospital, London, UK
`FrankJ. Rauscher,III ..........4.....istar Institute, Philadelphia, PA
`John C. Reedwoe Banna Distitute, La jolla, CA
`
`Marcel Rozencweig.......0-.Bristol-Myers Squibb Co., Princeton, NJ
`NagahiroSaijo.............National Cancer Center Research Institute,
`Tokya, japan
`
`Edward A Sausville..... jeeNCL Bethesda, MD
` Jan H. Schornagel .........0cece ee Netherlands Cancer fstitute,
`Amsterdam, The Netherlands
`
`Makoto Taketo................-......0 University of Tokyo, Tokyo, Japan
`Chris H. Takimoto ws. seccesseseectseeccsisennnnendGh, Bethesda, MD
`
`Masaaki Terada.....................National Cancer Center, Tokyo, Japan
`Jaap Verweif......Rolterdam Cancer Centre, Rotterdam, The Netherlands
`Paul Workman........fnstitute of Cancer Research, Sutton, Surrey, UK.
`
`“Ken Yamaguchi..............National Cancer Ceriter Research Institute,
`7
`Tokyo, fapart
`Margaret Fotii......ccccsseseeeseesceees wow AACR, Philadelphia, PA.
`Heinz H. Zwierzina............Medizinische Klinik, Innsbruck, Austria
`Giuseppe Giaccone....,..,.......ree University Hospital, Amsterdam,
`-
`The Netherlands
`Raffaella Giavazzl...............-....Marto Negri Institute, Bergamo, italy #
`Tona M. Gilmer..........Glaxe Wellcome, Research Triangle Park, NC -
`
`Gary B. Gordon oven oeale & Company, Skokie, i
`Louise Barmetl Grochow «0.0... ccceeeeees
`vee NCE Rockville, MD
`
`Axel-R. Hanauske.......cccceeeeeCenter for Hematology/Oncology,
`Munich, Germany
`
`Michael John Hawkins ............... Washington Cancer Institute,
`‘
`Washington, DC
`
`Susan D. Hellmann a... Genentech, South San Francisco, CA
`Waun Ki Hong ........07 M.D, Andersen Caricer Center, Houston, TX
`Susan 5. Horwitz......Albert Eirtstein College ofMedicine, New York, NY
`Stephen B. Howell cascearesen University ofCalifornia, San Diego, CA
`
`SPECIAL COMMITTEE
`FOR REVIEW OF ABSTRACTS
`Loretta Itri
`
`Joseph R. Bertino
`Bruce A. Chabner
`
`Michaele C. Christian
`
`Nei] J. Clendenina
`Susan P. C. Cole
`
`Janice P. Dutcher
`
`W.Gillies McKenna
`
`Martine J. Piccart
`Herbert M. Pinedo
`
`Frank J. Rauscher, III
`John C. Reed
`
`Alexander M. M. Eggermont
`
`Edward A. Sausville
`
`Susan D. Hellmann
`
`Jaap Verwelj
`
`Waun Ki Hong
`
`14
`
`I P
`
`roceedings of the 1999 AACReNCI*EORTC Internaticnal Conference
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`Abstracts: Poster Session 1 3729s
`Clinical Cancer Research # Volume 5 ® November 1999 (Supplement)
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`#3=©PNU-159548: predicting human MTD fron praclinical data.
`POSTER SESSION 1
`Sassa Cristiana, Da Jonge Maja J.A,, Ghielmini Michele, Cofajorl Elena,
`SECTION 1: PHASE | CLINICAL TRIALS: NEW
`Grossi Pielro, Moneta Donatella, 7urlo MariaGrazia, Vanveij Jaap. 10S,
`AGENTS, ANTIANGIOGENESIS, AND MOLECULAR
`Bellinzona, Switzerand: Rotterdam Cancer institute, Holterdam, The Neth-
`ENDPOINTS
`erfends; Pharmacia & Uplohn, Milano, Haly.
`A medel for predicting MTC [In humans and passibly gutding dose
`escalation in phase | stucias with cytotoxic agents was suggested by
`Parchment (1998) for compounds having myelotoxicity as DLT in the
`preclinical models, Tha model is based on the use of in viira hamatotoxl-
`cological dala associated with in vive systemia exposure In tha same
`species, PNU-159548Ia the lead compound of anovel class of cylotoxic
`agents (alkyeyalines) with a promising spectrum of antitumoractivity. The
`compound was judged to be a good candidate for a prospective validation
`of this model, based on its safety profile (DLT primarily leukopenia and
`granuloeytopenia} and dose-preportionallty for both parent drug and active
`metabolita up to MTD in animals. The relative in vitro myelotoxicity was
`tested in mouse, dog and human bene marrow precursors, thus identlfying
`inter-species differences in drug tolerance (mouse > human > dog) and
`the IC$0 ralios for CFU-GM were used to adjust the target AUC and predict
`MTDin humans. PNU-159548 is currently tested in two phase | studies
`with an Initial accslerated ttration design followed by conventional dose
`escalation. PKs of PNU-159549 and Its major aclive mataholite (13-dihy-
`dro derivative) are assessed during thefirst cycle In all patients (pls). in
`vitra myelotoxicity of pts plasma‘is tested In one study to: evaluate the
`cytetoxicily of ihe compaund and of known/unknown metabolites in ex-
`perimental conditions similar to thosein the clinical setting. Overall 40 pls _
`have been treated so far at doses ranging from 1 to 14 mg/m? (ongoing}.
`To date, (ha MTD has bean reached (14 mg/m?) In pretreated pts in one
`study. Bone marrow |s confirmed io be a primary target in humans, with —
`thrombocytopenia and neutropenia observedstarting frorn 6 mg/m?. How-
`ever, al variance wilh the observation in animals and based on current
`results, thrombocytopenia seems to be dase-IImiting. PK of bolh parent
`drug and metabolite appear to be linear at the tested doses. Preilminary
`conclusions an the yalicity of ihe predictive model, and Identification af
`critical factors, such as prolein binding, mélabollta contribution, drug-
`clearance rate, will be presentad and ciscussed.
`
`_
`
`Troxacitablne (BCGH-4556}, a nuclaoside anateg wilh distinct
`#10
`stereochemical, pharmacologic and pharmacokinetic characterlaties
`Is tolerable and active In phase | atudles: the NCI-C CTG experiences.
`Moore M, Balanger K, Dionne J, McLean M, Jclivet J, Proulx L, Baker 5,
`Waloman N, Seymour L. ND Program, NCIC CTG, Kingston, BlioChem
`Pharma inc, Canada,
`Troxacilabine (TROX) is a dioxolane L-nucleoside analog with broad
`cytotoxic activity in in-vitro and in-vivo models. Othar than its unique
`slereochemistry, TROX has distinct pharmacology: It undergoes Intracel-
`lular phospheryletion (predominant Intracellular form is the diphosphate)
`but Is resistant to deamination and ls a complete DONA chain terminator.
`These interesting characteristics led to the Initlation of dose-sesking pahase
`i studies in North America, The phase | study conducted in Canada sought
`to define the safaty and PK profile of troxacitabine When administered as
`a single 30-minute Infusion every 3 weeks,
`45 patienls (pis) with acceptable organ and marrow functlon who had
`received no more than 2 prior chemotherapy (CT) regimens were entered
`to 13 dose levels (DL's) and received 150 cycles of troxacitabine. The
`maximum tolerated dose (MTD) was reached at 12.5 mg/m?, and ihe dose
`recommended (RD) for phase Il siudies was 10 mg/m. Dose limiting
`toxicities in the first cycle were confined lo self-limited grade 4 granule-
`cytapenia; some patients experienced a generalized maculopapuler rash
`preventable by corticosteroids, At 10 and 12.5 mg/m?, hand-foot syn-
`drome occurred in 6 of 13 patients {grade 3 in 2 and grade 2 in 4 palients),
`2 patients had traatment discontinued. Two patlents at lhe AD had con-
`firmed partial rasponses {renal cell carcinoma and carcinoma of unknown
`origin); overall 18 patlents had stable clsease with median duration of 6
`months (range 1.4-18.7 mths), PK’s werelineer and at 10 mg/m? AUG was
`1886 ng - h/mi: C2, 882 ng/ml; clearance 159 mL/min, and T,,. 12 hrs.
`Clearance was predominantly renal, and drug and creatinina clearance
`were slrongly correlatad. Other schedules that have been examined in-
`clude a dally x 5! (AD 1.5 mg/m? iv x 5) and a weekly” (RO 3.2 mg/m’).
`In view of the PK profile of the compound, the convenlence of ihe 3 weekly
`schedule and the demonstrable activity al ihe RD using thls schedule, a 30
`minute infusion every 3 weeks of TROX 10 mg/m® has been taken forward
`#40=The activity and pharmacokinetics of rebeccamycin analog
`inle phaseIl studies. The NCIC CTG has |nitated phaseI] studies in renal
`(NSC 655649} In cancerof thebillary tract during a phaseI irlal. Dowlati
`cell and nonsrnall call lung cancer; interim safety and efficacy data will be
`4, Majka S, Heppel C, Ingalls S, Spiro T, Garson S, Ivy P, Willson JI,
`presented.
`Sedransk N, Remick SC. Developmental Therapeutics Program, Ireland
`’ Stephenson J, Baker SD, Johnson T et al. Proc Am Soe Clin Oncol 1999
`? Canova A, Yee L, Baker S$ at al, Proc Am Soc Clin Oncol 1999
`Cancer Center, Case Western Aesarve University, Claveland, OH and NCI,
`Bathasda, MD.
`—
`NSC 655648 is a water soluble analog of the antitumorantibiotic rebec-
`camycin, which intercalates into DNA and inhibits the catalytlc activity of
`#2=~Phase | and pharmacokinetic (PK} study of a novel cytotoxlc
`topoisomerase IL We performed-a phase| trial to datermina the feasibility
`agent, PNU-159548,in patients (pts) with solld tumors. De Jonge Mala
`of administering rebaccamycin analog (RA) as a daily * 5 schedule q21
`J.A., Worlelboer Monica, van der Gaast Ate, Colajori Elena, Valota Olga,
`day and to study the pharmacokinetic (PK) profile. We have previously —
`Florenlin{ Francesco, Verwell Jaap, Sessa Cristiana. /OS!, Sellinzona, Swit-
`reported the preliminary data from ihls trial (Proc. ASCO 1999, a694). In,
`zorland; Rotterdam Cancer Institute, Fiottardam, The Netherlands; Phar-
`this-trial we have observed significant activity in cancerof the billary tract.
`macia & Uinjohn, Milano, italy.
`PNU-159544 /s lhe laad compound from a novel cytotoxic class (alky-
`Four pts with gallbladder (GB) cancer and ona patient with cholangiocar-
`cinoma (5/27 pts} have been enrolled on this Irial across all dose levels,
`cyclines}, with a unique mechanism of action combining alkylation and:
`Minor response and prolonged stable disease (SD) has deen seen In each
`Intercalation, and lacking cross resistance with MDR-related driigs, alky-
`of ihese pts. Furthermore, all pts experienced improvementin their per-
`lating agents and topo-| Inhibitors. In preclinical studies side-effects mainly
`formance status. Ona pt wilh GB cancer treated at dose leval one had a
`consisted of hematologic and gastrointesiInal loxlcity. Two phase | and
`phermacologlc trials invesiigate the |}.\V¥. administration of PNU-159548
`47%,fasponse and is continuing therapy for >2 years. One pl with GB.
`‘cander had SD x 9 mos bul died of sepsis and livar abscesses. One pt with -
`once avery 3 weeks In patlents with solid tumors, Starling dose, 1 ma/m?,
`was escalated with an Initlal accelerated phasa (1 pt/dose level) followed
`“GB cancer had SD X 10 mos and hen progressed. One pt wilh GB cancer
`Had SD x 5 months and was Ihen laken off sludy beaauseof Increase in
`by conventlonal dase escalation In 3-6 pt cohorts. The PKs of PNU-
`billrubin ihal needed a stent placement. This pt had a CA19,9 that de-
`159548 and Its active 13-dihydro derivative(PNU-169884) were assessed
`after the first administration by LC/MS-MS.
`creased fram 2200 prior to treatment to 700 after cycle 5. The only pt with
`Overall, 40 pts are entered, 39 pls (median age 55 years; median ECOG
`chalangiccarcinoma has SD x 4 months and is continuing therapy. AA
`exhibits linear PK’s and compartmant modeling reveals that the PK best
`PS 1} and 66 cycles ara evaluable for loxlcity. Dose levels studied were 1,
`fits a 3-compartment model with a t1/@a = 0.2 hr, t1/2B = 3.3 hr and
`2, 4, 6, 9, 12 and 14 (ongoing) mg/m*, Non-hematological toxicities con-
`t1/2y = 100 hr. Preliminary dala suggasled entarchepalle circulation. Blle
`sisted of nausea and vomiting and were matnly mild, At several dose levels
`obtained from one pl on day 10 shewed levels 10-fold greater than ihe
`(2, 6, 9 and 12 nig/m? [1 pt each} and 14 mg/m? [2 pts) a histarnine release
`simullaneous plasmalevel suggesting significanl and prolonged exposure
`syndrome (fever, chills, erythama, facial edema and dyspnoea) was ob-
`served during drug administration, which recovered elther spontaneously
`of ihebiliary lract to RA. Except for one pt, there was no difference In the
`or with antl-histamine therapy. Standard prophylaxis is so far not required.
`infusion phase cata for pis with cancer of the billary tract vs other cancer
`Thrombecytopenia was the main hematologic toxicity and occurred In
`types, This patient had substantially more AA in’the day 2 through day 5
`pre-infusion plasma. She was admitted on day 8 with biliary stent closure
`18/40 pts during thefirst cycle, starting from 6 mg/m? and was DLT (PLT
`and therefora this deviation may have been due to progressive slent
`50 — 25 x 10°L for 5 days or <25,0 * 10°/L) at 6 (1/6 pts}, 9 (1/70), 12
`closure during the days of Iraatment. End of infusion peak plasma con-
`(1/9) and 14 mg/m? (9/8). Two pts with NSCLC had stable disease for 18
`and 19 weeks, respectively (one pt still on treatment). PK data on PNU-
`centrations of AA did nol increase in proportion ta dose escalation in pts
`159648 show a pclyexponential decline, with at). of 3-7 h and no
`with or withoutbiliary lract cancer. This iIncling is consistent with saturation
`significant deviation from linaarity. C,,,, of PNU-169884is reached 0.7—-1.2
`of plasma protein RA bincing capacity in conjunction with rapid distribution
`of unbound drug to some other components. PK modeling showed similar
`h after treatment and plasma concentralions decline similarly to lhe parent
`rasults between pis with and without cancarof thebiliary tract, In conclu-
`drug. The systemic exposure to the matabclite is slightly higher than that
`sion, RA demonstrates activity In cancer of lhe billary lract, mostlikely by
`to PNU-159549. The MTD of PNU-159548 for pretreated pts is 14 mg/m
`‘In one study; it has net been reached yet for untraated pis and the sludies
`virtue af prolonged exposure of the biliary tract to this drug. (Supported by
`NIH grant nos. 2 UO1 CAG2502-06).
`remain in progress.
`15SS
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`Proceedings of the 1999 AACReNCI*EORTCInternational Conference
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` | ar
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`ehyng.
`
`-
`
`o/3
`6
`of
`6
`i408
`7
`0/3
`9
`2/3 -fabrila neutropenia,
`“ga 4 neutropenia &
`thrombocytopenia
`1/4 -gd 4 neutropenia &
`10
`4
`160 mg/m? x 5
`,
`thrombocytopenia
`{currently explored}
`‘
`& od 4 mucositis
`
`3
`3
`3
`3
`3
`
`.
`
`Preliminary PK results indicate that E7070 displays a long half-life Ts and
`a large volumeofdistribution. At dose-levels above 52 x 6 mg/m? Gmax
`increases propertianally while AUG increases more than dose-proporlional
`and the clearance & Vd,,, tend to decrease suggesting a non Unearity in the
`PK's. So far, no response is reporled.
`
`weamewefo
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`Proceedings of the 1999 AACR*NCI®*EORTC International Conference
`
`Clinical Cancer Research ¢ Volume 5 * November 1999 (Supplement)
`3730s Abstracts: Poster Session 1 continued
`ave
`
`Dose-Level
`40 mgm? x 5
`
`BLT's
`146 -atrial fibrillatlan at
`2nd course
`
`13 mgim? = 5
`26 mg/m? x 5
`52 mg/m? x 5
`104 mg/m? x 5
`200 mg/m? x 6 (MTD)
`
`#7©CCI-779, A new Rapamyeln analog, Has Antitumor Act