1
`
`OSI 2024
`APOTEX V. OSI
`IPR2016-01284
`
`

`

`Thirty-Fifth
`
`Annual Meeting of the
`
`American Society of Clinical Oncology
`
`May 15-18, 1999
`
`Atlanta, Georgia
`Program/Proceedings
`
`
`
`2
`2
`
`Copyright 1999 American Society of Clinical Oncology
`This mate-rial W‘aS-Eflpifid
`at: the NLM and may be
`
`

`

`Editor: Michael C. Perry, MD
`
`Associate Editor: Clay Anderson, MD
`
`ASCO Science and Education Program:
`
`Director: Michele K. Dinkel
`
`Assistant Director: Laura K. Ulepic
`
`Coordinator: Nicole Johnson
`
`ASCO Publications:
`
`Managing Editor and Director: Deborah Whippen
`Editorial Assistant: Nathan Grace
`
`The American Society of Clinical Oncology Program / Proceedings (ISBN 0-9664495-4-1) is
`published by the American Society of Clinical Oncology, Alexandria, VA 22314. The 1999 issue
`is produced and printed by Lippincott Williams & Wilkins, 351 West Camden Street,
`Baltimore, MD 21201-2436.
`
`Editorial correspondence and production questions should be addressed to American
`Society of Clinical Oncology Program / Proceedings, American Society of Clinical Oncology
`Publications Department, 850 Boylston Street, Chestnut Hill, MA 02467. Telephone:
`(617)739-8909. Fax: (617 )739-8541. Email: ascopubs@asco.org.
`
`Single issue rate, $50.00. For all areas outside the United States and possessions, there is
`an additional charge for surface delivery of $10.00. For airmail delivery, add $15.00.
`
`Prices are subject to change. Back volumes exist and are available at previous published
`prices. For further information, call (617)739-8909.
`
`Copyright © 1999, American Society of Clinical Oncology. All rights reserved. No part of this
`publication may be reproduced or transmitted in any form or by any means, electronic or
`mechanical, including photocopy, recording, or any information storage and retrieval system,
`Without written permission by the Society.
`
`
`
`The American Society of Clinical Oncology assumes no responsibility for errors or omissions
`in this document. The reader is advised to check the appropriate medical literature and the
`product information currently provided by the manufacturer of each drug to be administered
`to verify the dosage, the method and duration of administration, or contraindications. It is
`the responsibility of the treating physician or other health care professional, relying on
`independent experience and knowledge of the patient, to determine drug, disease, and the
`best treatment for the patent.
`
`Abstract management and indexing provided by Marathon Multimedia Inc, Northfield,
`MN. Electronic page composition and print production provided by Lippincott Williams &
`Wilkins, Baltimore, MD, and the Mack Printing Group, Easton, MD.
`
`Copyright 1999 American Society of Clinical Oncology.
`3
`3
`Th is material was copied
`at the NLM and may be
`Su Dian Uzifiepxyright Laws
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`

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`Contents
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`Program and Proceedings Information
`ASCO OnLine (www.asco.org) Information .
`ASCO Officers and Directors .
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`Committee Rosters .
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`Highlight Sessions
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`Opening Ceremony .
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`Plenary Session .
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`Award Recipients .
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`GeneralInfinwnafion .
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`ASCO Shuttle Service .
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`Adult Leukemia and Lymphoma .
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`Bone Marrow Transplantation/Cytokines .
`BreastCancer .
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`Central Nervous System .
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`Clinical Pharmacology .
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`Gastrointestinal Cancer .
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`Genitourinary Cancer .
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`GynemflogmalCancer .
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`Health Services .
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`Immunobiology and Biologic Therapy .
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`Indexes
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`Author Index .
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`

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`
`
`Dose
`Level (mg)
`50 single D1
`50 multiple D14
`100 single D1
`100 multiple D14
`150 single D1
`150 multiple 014
`
`Tli2
`(hr)
`34
`39
`
`53
`
`Thiax
`(hr)
`
`993????”mmiaxrwof
`
`190
`128
`273
`
`AUC
`(ng*hlml)
`1301
`4519
`
`12784
`
`These results indicate that potentially biological relevant concentrations of
`ZD1839 are achievable and feasible and that oral daily ZD1839 is
`well-tolerated at doses up to 225mgjday for 14 days.
`
`388a
`
`HEAD AND NECK CANCER
`
`Proc
`
`eedings of ASCO Volume 18 1999
`
`*1499
`
`wth Factor Receptor (EGFR)
`y of Epidermal Gro
`Phase I Dose Escalation_stud
`4 in Patients with Advanced Solid
`_
`GP 358,};705udae, F. Wirth, L. Gaynes, m.
`Tyrosine Kinase (TK) Inhibitor
`' M, Huang, LE. Schn/pper. Beth
`Tumors. D.D. Kar , S.L. Si/berman.
`Posner, mm; H. Koon, M. Bergman:
`MA; Pfizer Inc. Groton, CT.
`'
`ICenter, Boston,
`I
`.
`.
`Israel Deaconess Med/ca
`t that directly Inhlb‘ts EGFR
`CP-358,774 is a novel oral
`id tumo,s_ Preminical
`,
`I
`TK. a receptor that is over—e
`,ts EGFR autophosphorylation and
`studies reveal that CP—358,774 Inhlsbland mouse xenografi models The
`Ce“ DVO'iferatiO" in human Ge“ Ime
`TD,toxicity, and pharmacokinet_
`I
`'
`'
`'al were to define the M
`.
`i)cbsle(%tll(v)e:foif~teh;:lynadministration of CP-358,774. Escalatlng doses were
`t of 4 weeks to cohorts of 3 pts
`'
`'
`d
`all once every week for 3 cu
`I
`'
`‘
`ngdglssetéggrireeri pts (median age 53.5yrs, 12.M/6.F, medlan Karnofsky
`o
`-
`a solid tumors (7 lung. 3 prostate, 3
`performance status 80 /o) wrth advance
`1 liposarcoma) who had received
`d neck, 1 breast, 1 renal,
`I
`2°$°enéi2nhgfc2j iirrange 1—3) prior treatment regimens were trefatelil at 5 doses
`(100 220 400 800, 1,000 mg) for a maxrmum perm? 0‘
`(~9ng No
`.
`‘f'canttoxicities were observed at 100 and 200 mg. OXICI Ies 0 served
`Slgm I
`as Virtually universal but
`in subsequent cohorts included fatigue. Wh'ChXV’ Gr 2 maculo_papular
`mild’ Grade (Gr) 2 headaCh ’ and Gr 2 diarrhea. One pt on IOOOmg
`(acneiform) rash, Gr 2 nausea,
`ional pts received looOmg and 2/3
`develo ed Gr 3 diarrhea, thus 3 addit
`develoged Gr 2 diarrhea. Pts continue to be accrued at the 1200 mg (toge-
`Preliminary PK analysis reveals large intra- and inter subject variability,
`‘
`'
`'
`n when doses are
`althou h relativer dose proportional increases are see
`escalafed from 100 to 1000 mg weekly.vAUCo-24 ranged from 21.3
`ug.hr/ml to 116.0pg.hr/ml, Cavg from 0.9 ug/ml to 4.8 pg/ml; and cma)<
`from 1.5pg/mlto 7.1 ug/m
`dat Day 1).The ratio of Day
`8 to Day 1 AUCO_24 ranged from 0.66 to 1.21. Thus. CP—358.774 is a well
`when administered weekly in doses. upto 1,0‘00mg,
`to'eramd oral agent
`rdose escalation Is continuing.
`The MTD has not been reached, and furthe
`
`*1501
`
`Phase I Trial of Chimerized Anti-Epidermal Growth Factor Receptor (Anti-EGFr)
`Antibody in Combination with Either Once-Daily or Twice-Dally Irradiation for
`Locally Advanced Head and Neck Malignancies. Mark P. Ezekiel, James A.
`Bonner, Francisco Robert, Ruby F. Meredith, Sharon A. Spencer, Albert F.
`LoBug/io, Harlan W. Waksal. ImClone Systems Incorporated, SomerviI/e,
`NJ.
`
`*1498
`
`the Epidermal Growth Factor
`Dose and Schedule-Duration Escalation of
`Receptor (EGFR) Tyrosine Kinase (TK) Inhibitor CP-358, 774: A Phase I and
`Pharmacokinetic (PK) Study. L.L. Siu, M. Hida/go, J. Nemunaitis, J. Rizzo,
`J. Moczygemba, S.G. Eckhardt, A. To/cher, L. Smith, L. Hammond, A.
`Blackburn, T. Tensfe/dt, S. Siiberman, D. D. Von Hoff, E. K. Rowinsky. Pfizer
`/nc., Groton, CT.
`CP-358, 774 is an oral quinazolin compound which disrupts cellular signal
`transduction and triggers apoptosis via direct inhibition of EGFR TK. At
`nanomolar concentrations, CP—358, 774 inhibits purified EGFR TK and
`reduces EGFR autophosphorylation in intact tumor cells, with a selectivity
`of >1000-fold over other human TKs. Based on continuous oral dosing
`studies using xenograft models the projected target average plasma
`concentration (Cavg) for clinical efficacy is 500 ng/ml. This phase I study
`was designed to assess the feasibility of administering CP—358, 774 on
`prolonged oral dosing schedules and to determine if biologically relevant
`concentrations are sustainable. Pts on Leg 1 receive CP-358, 774 on 3
`consecutive d per wk for 3 wks followed by 1 wk of rest. Pts on Leg 2 receive
`CP‘358, 774 on d 1,
`then after a 2-d washout period, drug is given
`continuously for 3 wks followed by 1 wk of rest. To date, 27 pts with solid
`cancers (M/F 12:15, median age 56, median KPS 90%) have completed
`61 courses on these schedules: 9 pts/23 Courses on 3 dose levels in Leg 1
`(25 mg/d, 50 mg/d and 100 mg/d), l8 pts/38 courses on 5 dose levels in
`Leg 2 (50 mg/d, 100 mg/d, 150 mg/d, 200 mg/d and 100 mg bid).
`Dose~limiting gr 4 diarrhea was encountered at the 200 mg/d level in Leg 2,
`and subsequent cohort expansion to 6 pts resulted in 2 pts with gr 4 and 4
`pts with gr 1-2 diarrhea. An intermediate dose level of 150 mg/d was added
`with implementation of intensive IOperamide therapy upon the first sign of
`diarrhea, and 2/3 pts had only gr 1 diarrhea. Accrual is ongoing at 200
`mgld or 100 mg bid with Ioperamide support for diarrhea. Gr 1-2 acneiform
`rashes limited to the upper body have been observed in 9 pts thus far in Leg
`2, with histopathology of skin biopsies showmg subepidermal neutrophilic
`infiltration and epidermal hyperproliferation. Other toxicities have been
`mild and include headache, nausea, fatigue, and transient rises in serum
`bilirubin and transaminases. Preliminary PK analysis reveals an approxi-
`mate 2-fold range in inter-subject variability in exposure. Dose-related
`increases in exposure were obServed; mean Cavg values following continu—
`ous daily dosing at the 50, 100 and 200 mg/d levels in Leg 2 were 432
`(n=3), 973 (n=3) and 2120 (n=5) ng/ml,
`respectively. Dose-related
`accumulation in exposure was observed (AUC0.24 ratio d 24/d 1=1.2-4.8).
`The target Cavg of 500 ng/ml was achievable at dosesalOO mg/d on a
`well-tolerated schedule.
`
`*1500
`
`ZDIB39, an Ural Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase
`Inhibitor: First Phase 1, Pharmacokinetic (PK) Results in Patients. L_isg
`Hammond, M. Ranson, D. Ferry, M. Kris, H. Kelly, J. Ochs, S. Averbuch, E.
`Rowinsky, Zeneca Pharmaceuticals, Wilmington, DE,
`ZD1839 is a potent and selective inhibitor of the EGFR-associated tyrosine
`kinase involved in signal transduction and mitogenic stimulation. The |C50
`for Z01839 enzyme inhibition of EGFR isolated from A431 vulval squa-
`mous carcinoma was 10.3-35.0ng/ml. In preclinical studies that served as
`the impetus for this study, prolonged daily oral dosing resulted in tumor
`growth inhibition and regression. This present study was designed to assess
`the feasibility of administering oral ZD1839 daily for 14 consecutive days
`to cancer patients with tumors that are known to commonly overexpress
`EGFR. At the first dose level (for PK data purposes only), patients received
`one dose of ZD1839 followed by a seven-day washout prior to consecutive
`ZD1839 daily dosing. To date, 27 patients (median age 51.5 years, range
`28—68 years, median KPS 1) have received 38 courses atthe following dose
`levels: 50, 100 150 and 225mg/day. Drug—related toxicities (all Grade 1)
`have included anemia, leukopenia, uveitis (n=1 patient), nausea, emesis,
`HA, dry mouth and skin (n=1 patient). PK parameters (mean) for single
`and multiple dosing iterations are:
`
`Preclinical studies have revealed that combined treatment of anti-EGFr
`(C225) and irradiation results in radiosensitization in squamous cell
`carcinomas that overexpress epidermal growth factor receptor (Saleh et al,
`Proceedings Am Assoc Can Res, 37:612, 1996). Therefore, a phase I trial
`has undertaken to determine the tolerability of combined C225 and
`irradiation for patients with locally advanced (unresectable) head and neck
`malignancies. A standard dose escalation procedure was utilized with 3
`patients entered at each increment of C225 given with 70 Gy (2.0 Gy given
`once-daily: 2 Gy q d) of radiation therapy with the final 3 patients receiving
`76.8 Gy (given twice-daily: 1.2 Gy BID) with noincrement in C225 dose.
`C225 was delivered as a loading dose of 100-500 mg/m2 l.V. followed by
`weekly infusions of 100-250 mg/m2 x 7. Sixteen patients were entered on
`the trial with the following primary sites: oropharynx (7). oral cavity (5),
`larynx (1), hypopharynx (3). Thirteen patients had stage IV disease and 3
`had stage III disease. One patient was not evaluable for toxicity or response
`due to recent completion of
`treatment and another patient was not
`evaluable for response due to an anaphylactic reaction (grade 4) during the
`initial C225 treatment. The latter patient subsequently discontinued
`protocol
`therapy. Nine (56%) patients experienced irradiation«related
`grade 23 mucositis (one was grade 4) and five (31%) patients experienced
`C225 and/or irradiation related grade 3 skin toxicity (primarily related to a
`follicular rash). No C225 dose delays were required and in general, the skin
`toxicities recovered completely orto grade 1 or 2 duringtreatment or shortly
`thereafter. The irradiation-related toxicities were not exacerbated by adding
`0225 to radiation therapy. There was no increase in frequency or severity,
`nor was there any need for unexpected treatment medication or procedures,
`demonstrating that this combined therapy is both safe and well-tolerated.
`Of the 15 evaluable patients, 14 (93%) achieved complete responses
`based on physical and endoscopic examination. These results are highly
`encouraging when compared to published rates of complete response
`ranging from 20% to 50% in similar patients treated with irradiation alone.
`5
`Supported by ImClone Systems Incorporated.
`This mate-rial was {applied
`at: the NLM and may be
`So Inject US {labyright‘ Laws
`
`