A Supplementto
`v.12
`W1 ON106K
`
`1998
`e.01—.~
`NO. 1
`P0060102
`Tze ONCOLOGY
`‘
`ae
`En a, © SEO: SROC
`
`02/27/98
`
`
`.
`
`JANUARY 1998
`
`
`
`VOL 12 * NO 1 (SUPPLEMENTNO1
`Paclitaxel in Breast Cancer:
`Putting the Evidenceinto Practice
`
`Proceedingsfrom the Pan European Interactive Forum
`Lisbon, June 28, 1997
`
`
`
`Full contents on pages 5 through
`
`7
`
`RENEDaa
`
`
`This material was conied
`
`(cid:43)(cid:82)(cid:86)(cid:83)(cid:76)(cid:85)(cid:68)(cid:3)(cid:89)(cid:17)(cid:3)(cid:42)(cid:72)(cid:81)(cid:72)(cid:81)(cid:87)(cid:72)(cid:70)(cid:75)(cid:3)
`Hospira v. Genentech
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:26)(cid:16)(cid:19)(cid:19)(cid:27)(cid:19)(cid:24)(cid:3)
`IPR2017-00805
`(cid:42)(cid:72)(cid:81)(cid:72)(cid:81)(cid:87)(cid:72)(cid:70)(cid:75)(cid:3)(cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87)(cid:3)(cid:21)(cid:19)(cid:24)(cid:19)
`Genentech Exhibit 2050
`
`
`
`Editor
`
`Larry Norton, MD
`Chief, Breast/Gynecology Oncology Services
`Memorial Sloan-Kettering Cancer Center
`
` rn .
`Withpresentations by:
`|om2s23woP
`y= aS
`PierFrancoConte,MD,etal Hans-JoachimLiick,Mp,pub,etal
`Ao Os
`UO OncologiaMedica
`Medizinische Hochschule
`2z <Ze
`ienrgeFountzilas, 7“ aval Miguel Martin, Mb,Pnb, etal
`mos
`eThedeanolile
`University Hospital
`>
`Aristotle University
`a on
`Oe
`at
`Tie
`of Madrid
`Luca Gianni, MD
`Istituto Nazionale Tumori
`James O'Leary, MD,et al
`The Kaplan Comprehensive
`Clifford A. Hudis, MD
`C
`“ Center
`Memorial Sloan-Kettering
`anger
`SALtN
`Cancer Center
`Andrew D. Seidman, Mp
`Memorial Sloan-Kettering
`Ute Klaassen, MD,et al
`Cancer Center
`West German Cancer Center
`
`1
`
`

`

`Paclitaxel in Breast Cancer:
`Putting the Evidence into Practice
`
`Proceedingsfrom the Pan European Interactive Forum
`Lisbon, June 28, 1997
`
`
`
`
`
`Editor
`
`Larry Norton, MD
`Chief, Breast/Gynecology Oncology Services
`Memorial Sloan-Kettering Cancer Center
`New York, New York
`
`
`
`This mares HRRIEEEMENT NO |
`atthe NLM and may be
`Subject US Copyright Laws.
`
`* JANUARY 1998 * ONCOLOGY
`
`2
`
`

`

`
`
`RamYomEEE ama og ERY Se
`
`9S MANORINE enn aaNENy
`
`JAMES F. MCCARTHY
`Editorial Director
`
`CARA H. GLYNN
`Assistant Editorial Director
`
`ELLEN OKIN POWERS
`Managing Editor
`
`ROSEANNE SZCZEPANOWSKI
`Assistant Managing Editor
`ANDREW NASH, JUNE SKINNER
`Senior Editors
`
`EDWIN S. GEFFNER
`Consulting Editor
`
`GAIL VAN KOOT
`Editorial Coordinator
`
`CHRISTINA FENNESSEY, LOIS FRIEDMAN
`Assistant Editors
`
`MADELINE MCCARTHY
`Editorial Assistant
`
`PublishingStaff
`
`LISA KATZ
`Creative Director
`
`MIA LIPP
`Assistant Art Editor
`
`JEANNINE CORONNA
`Production Director
`
`JOAN DETERS
`Production Manager
`NANCYM.FINN
`Assistant Promotions Editor
`
`STACEY ZEBROWSKI
`Classified Advertising Editor
`
`TARA A. FOWLER
`Project Coordinator
`
`MARY SCHULDNER
`National Sales Manager
`
`ANTHONY CUTRONE
`National Sales Representative
`
`
`
`EVELYN A. FOSELLA
`Administrative Assistant
`
`GERALDINE GENTILE
`:
`oat
`Director of Operations
`:
`ROBERT C. CANALE
`Publisher
`
`LOUIS MORRIS, PhD
`Regulatory Affairs Editor
`FAY SYMONS
`
`Director, Educational Programs
`
`GEORGE ROSSETTI
`
`Senior Editor, Educational Programs
`
`TRACEY MADIO
`Business Manager
`
`GENTILE,JR.
`
`.
`
`JOHN . ae
`resicen
`
`Clinical opinions expressed in articles are those of the authors and do not necessarily reflect the opinions ofthe sponsor, advertisers, editors or the publisher
`and officers of PRR, Inc. ONCOLOGYstrivesto select knowledgeable, experienced authors and reviewersfor articles and to answerclinical queries fromreaders.
`However, neither the editors nor publisher can guaranteethe clinical advice offered.
`Readers must take into account that answersto clinical questions are formulated without benefit of personal examination of the patient andare based only
`on the information supplied by the physician making the inquiry. As our readers must surely appreciate, our editorial advisors, consultants, and reviewers
`cannot diagnoseor prescribe for a particular patient without actually seeing the patient. Thus, the general comments in this journal are based on the clinical
`experience ofthe authors, reviewers, and consultants and should not be construed as a formal consultation or specific recommendation for a particular patient.
`The authors, editors, and publisher take extreme care to be certain that drugs and dosage recommendations are precise and accurate. However,
`typographical errors can occur. Therefore, be sure to double-check all dosage schedulesin articles against the manufacturer’ s package information data, Also,
`dosages and methods of administration of pharmaceutical products mentioned by authors may not necessarily be the sameas thoselisted in the packageinsert.
`Such dosages and delivery methods mayreflect the clinical experience of the author or authors and/or mayreflect the experience ofother clinical investigators.
`ONCOLOGY (ISSN 0890-9091)—Contents copyrighted 1998 by PRR,Inc., 17 Prospect Street, Huntington, NY 11743. James F, McCarthy, Senior Vice
`President and Editorial Director; Louis Morris, Senior Vice President and Regulatory Affairs Editor; Fay Symons, Senior Vice President and Director,
`Educational Programs; Edwin S. Geffner, Vice President and Consulting Editor; Robert C. Canale, Vice President and Director of Marketing; John A. Gentile,
`Jr., President. All rights reserved. Special Patient Information Aids may be reproduced byanindividual physician for distribution in his or her ownpractice
`withoutspecific request to the publisher. One or twocopies ofarticles for personalor internal use may be made at no charge. Copying beyondthat number for
`personalorinternal use is granted by PRR,Inc., provided that a fee of 9¢ per page per copyis paid directly to the Copyright Clearance Center, 27 Congress
`Street, Salem, MA 01970(telephone: 508-744-3350). Such permission does not extend to copying for general distribution, for advertising or promotional use,
`or for resale, which require specific written permission from the publisher. ONCOLOGYis includedin Index Medicus, Excerpta Medica, EMBASE, and the CancerLit
`and Cancer Line databases at the National CancerInstitute.
`ONCOLOGYis published monthly by PRR,Inc., with publication offices at Huntington, NY 11743 (telephone: 516-424-8900). Subscription rates: domestic
`and Canada, $90 per year; foreign, $112 per year; students, $80 per year; single copies of this supplement, $14 each, Please notify PPS Medical Marketing
`Group, Inc. promptly of change of address (send old mailing label and new address). Standard Class paid at Huntington, NY 11743 and at additional mailing
`offices. Postmaster: Please send address changes (form 3579) to ONCOLOGY,c/o PPS Medical Marketing Group,Inc., 264 Passaic Avenue, Fairfield, NJ 07004-
`2595.
`
`Supported by an unrestricted educational grant from Bristol-Myers Squibb Company, Oncology Division, Europe.
`
`2
`
`ONCOLOGY « VOLUME12 * NUMBER 1
`
`¢ SHEPPESENHENTNQidd
`atthe NLM and may be
`Subject US Copyright Laws
`
`3
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`4
`
`

`

`aaSSeg
`
`Patient Population
`Between February 1996 and June
`1997, 30 patients were entered into
`this trial. This preliminary report de-
`scribes mature data on the first 16 pa-
`tients. The median age was 56 years
`(range 35-74 years); median Karnof-
`sky performance status was 90% (70%
`to 100%). Twelvepatients had received
`one prior chemotherapy regimen, and
`3 vs 96
`250/140
`MDACC
`four had received two. Ten patients
`eeee
`(63%) had received doxorubicin previ-
`ously. One half ofall patients had pul-
`monary or osseous metastases, 44%
`skin and/or lymph node metastases, and
`31% hepatic metastases. Patients had a
`median of two organ-system sites of
`metastases (range oneto three).
`aee
`Drug Delivery/Toxicity
`For the first 215 weekly drug infu-
`sions, the median numberof infusions
`per patient was 13 (range 7-22). There
`were only four instances where a week-
`ly infusion was held. The median de-
`livered dose intensity was 95 mg/m//
`week (range 80 to 108 mg/m?/week).
`AS we encountered minimal myelo-
`suppression, the weekly paclitaxel dose
`was.increased to 110-120 mg/m*/week
`initially (Table 2). This resulted in grade
`3 sensorimotor neuropathy in five of
`nine patients; hence, dose escalation
`beyond 100 mg/m?/week was subse-
`quently abandoned.
`Moststrikingly, despite the deliv-
`ery of 95 mg/m?/week of paclitaxel,
`neutropenia was either mild or non-
`existent for the vast majority of pa-
`tients (Table 3). Grade 3/4 neutropenia
`has been noted in 14% of patients and
`no episodesoffebrile neutropenia have
`been encountered. There has been a
`lack of cumulative neutropenia with
`up to 22 consecutive weekly adminis-
`trations of paclitaxel (Figure 2).
`Three patients without a prior his-
`tory of diabetes mellitus devel-
`oped hyperglycemia after weekly
`dexamethasone administration and were
`managedwith oral hypoglycemic agents.
`Acute hypersensitivity reactions war-
`
`
` Results
`
`Addressall correspondenceto:
`Andrew D. Seidman, MD
`Breast Cancer Medicine Service
`Division of Solid Tumor Oncology
`Memorial Sloan-Kettering Cancer Center
`New York, NY [0021
`
`
`
`
`
`
`
`Table 1
`
`RandomizedTrials Addressing Paclitaxel Dose and Schedule
`
`Study Group
`
`BMS 048
`
`BMS 071
`
`CALGB 9342
`
`NSABP B-26
`
`Dose(s) (mg/m*)
`
`Schedule(s) (h)
`
`135 vs 175
`
`175 =MTD
`
`175 vs 210 vs 250
`
`250
`
`3
`
`3 vs 24
`
`3
`
`3 vs 24
`
`BMS= Bristol-Myers Squibb; CALGB = Cancer and Leukemia Group B; MDACC = M. D. Anderson
`Cancer Center; NSABP = National Surgical Adjuvant Project for Breast and Bowel Cancers
`
`Table 2
`
`Dose Modification Schema: Definition of Paclitaxel Dose Levels
`N= 9?
`
`N=7?
`
`Level
`
`Dose (mg/m?’)
`
`Level
`
`Dose (mg/m?)
`
`3
`
`-2
`
`-1
`
`0
`
`+1
`
`+2
`
`60
`
`80
`
`90
`
`100
`
`110
`
`120
`
`“3
`
`-2
`
`-1
`
`0
`
`50
`
`60
`
`80
`
`100
`
`@Dose modification schema was modified after 5 of 9 patients with dose escalation above 100 mg/m?
`experienced grade 3 neuropathy(videinfra).
`
`(Figure 1). Dose modifications were }
`
`dose of 100 mg/m? every 7 days with-
`out interruption. Treatment was admin-
`istered in the outpatient clinic with a
`physician or chemotherapy nurse
`presentduring thefirst 15 minutes. Vital
`signs were monitored after the first 15
`minutes. All patients received standard
`prophylactic antiallergic premedication
`before each paclitaxel
`infusion. This
`consisted of dexamethasone 20 mg,
`orally at 12 and 6 hoursbefore paclitaxel
`administration and diphenhydramine 50
`mg, and cimetidine 300 mg,
`intrave-
`nously, 30 to 60 minutes before
`paclitaxel
`infusion. Treatment was
`planned to continue until disease
`progression or intolerable toxicity
`
`initially scheduled after every
`four infusions; however, after the first
`nine patients were treated,
`this was
`possible after every two infusions, as
`indicated in Table 2. Radiologic
`assessment of measurable disease
`was performed no less than every 8
`weeks.
`
`Pharmacologic Evaluation
`Pharmacologic studies were done
`during the first drug administration for
`14 patients. Serum samples collected
`at 0.5, 1, 3, 6, 25, and 28 hours after
`initiation of paclitaxel infusion were
`analyzed by high-performance liquid
`chromatography (HPLC)as described
`previously.[8]
`
`20
`
`ONCOLOGY * VOLUME 12 « NUMBER J ThS&UBPEEMENEMd
`atthe NLM and maybe
`Subject US Copyright Laws
`
`5
`
`

`

`Trial design
`
`
`
`
`
` ANC(x1000/uL)
`a
`altTet
`
`
`Figure 1: Trial design—Dose-dense paclitaxel 100 mg/m? via weekly
`1-h infusion.
`
`
`
`
`
`10
`
`
`
`
`
`ranting treatment discontinuation have
`not been noted. The complete toxicity
`profile is illustrated in Table3.
`
`Antitumor Activity
`To date, 6 of 15 evaluable patients
`have responded (40%; 95%confidence
`interval 16% to 68%). One complete
`remission in a patient with extensive
`cutaneous and subcutaneous chest-wall
`disease continues after high-dose con-
`solidation 11 months later. Partial re-
`sponses have beenobservedin liver[2],
`lungs, lymph nodes, and skin. Three
`responses have been noted in patients
`with prior anthracycline,
`two within
`three months of disease progression on
`doxorubicin. Four additional patients
`have experienced minor responses
`(25% to 49% reduction in bidimen-
`sionally measurable disease). One pa-
`tient with extensive hepatic metastases
`died of autopsy-proven pulmonary mi-
`crovascular carcinomatosis 18 hours
`after a first paclitaxel infusion.
`
`Pharmacologic Analysis
`Plasmapaclitaxel concentration as-
`sayed by HPLCrevealed a medianC,,,,
`of 4.75 UM (range 2.73-6.76), a median
`AUCof17.23 uM-h (range 9.34-22.35),
`tieB 12.23h (8.3-25.0). These parame-
`ters are well within the range necessary
`for in vitro cytotoxicity and are not very
`dissimilar from those seen with slightly
`higher doses (eg, 135 mg/m?) adminis-
`tered via 3-hour infusion.[9]
`
`Discussion
`
`
`
`
`123 45 67 8
`
`9 101112131415 16 1718 19 20 21 22
`
`Week
`
`This preliminary report is notable
`for significantactivity and a very favor-
`able toxicity profile for the weekly ad-
`ministration of paclitaxel via |-hour
`infusion at < 100 mg/m*/week. Despite
`the higher delivered dose intensity than
`with standard paclitaxel at 175 mg/m?
`(3 hours) every 3 weeks (95 mg/m?/
`week vs 58.3 mg/m’/week),less myelo-
`Figure 2: Absolute neutrophil counts, weeks 1-22. There has beenalack of
`suppression appears to occur with the
`cumulative neutropeniawith up to 22 consecutive weekly administrations of dose-
`present regimen. The resilience of mye-
`densepaclitaxelvia 1-h infusion.
`Joid precursors to repeated exposure to
`paclitaxelat this dose and schedule sug-
`gests that it is possible to uncouple drug
`delivery from bone marrow suppres-
`sion. The complete absence of febrile
`neutropenia and relatively shallow leu-
`kocyte nadirs permitted chronic weekly
`therapy without treatment interruption
`or growth factor support.
`Neurotoxicity became dose-limiting
`
`This material S956PBRENT NO 1
`atthe NUM and may be
`Subject US Copyright Laws
`
`+ JANUARY 1998 + ONCOLOGY
`
`21
`
`6
`
`

`

`SSee
`
`Table 3
`Toxicity (NCI CommonToxicity Scale)
`
`Toxicity
`
`Leukopenia
`
`Neutropenia
`
`Thrombocytopenia
`
`Fever
`
`Nausea
`
`Diarrhea
`
`Alopecia
`
`Neuro-sensory
`
`Neuro-headache
`
`Dermatologic
`
`Stomatitis
`
`Grade 0
`
`6 (40)
`
`9 (60)
`
`15 (100)
`
`14 (93)
`
`12 (80)
`
`9 (60)
`
`0 (0)
`
`3 (20)
`
`14 (93)
`
`11 (73)
`
`10 (67)
`
`Numberof Patients (%)
`3
`4
`
`2
`
`4 (27)
`
`3 (20)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`1 (7)
`
`13 (87)
`
`3 (20)
`
`0 (0)
`
`1(7)
`
`2 (13)
`
`3 (20)
`
`1 (7)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`5 (33)
`
`1 (7)
`
`0 (0)
`
`0 (0)
`
`1 (7)
`
`1 (7)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`Jf
`
`1 (7)
`
`1 (7)
`
`0 (0)
`
`1(7)
`
`3 (20)
`
`5 (33)
`
`2 (13)
`
`4 (27)
`
`0 (0)
`
`3 (20)
`
`3 (20)
`
`
`
`Arthralgia/Myalgia
`
`5 (33)
`
`4 (27)
`6 (40)
`0 (0)
`3(20)
`12 (80)
`Fatigue
`0 (0)
`0 (0)
`eeSSS
`
`0 (0)
`
`0 (0)
`
`8In patients whose dose was escalated over 100 mg/m?
`There were no episodesoffebrile neutropenia.
`
`when the weekly dose was increased
`above 100 mg/m?, but it was rarely
`significant at doses < 100 mg/m’. Dose
`reduction to 80 mg/m? allowed the con-
`tinuation of therapy in three re-
`sponding patients who experienced
`significant neurosensory dysesthesia.
`Recent data from Breier et al have
`showna lack of significant neurologic
`toxicity with weekly dosing of pacli-
`taxel
`at 80 mg/m? via
`l-hour
`infusion.[10]
`Cellular cytokinetic considerations
`imply that the shorter intertreatment
`intervals characteristic of dose-dense
`therapy should allow less opportunity
`for the emergence of drug-resistant
`clones.[5}] However, emerging data
`also suggest that antiangiogenic[11]
`and proapoptotic effects[12] of
`paclitaxel may be exploitable by this
`novel drug administration schedule.
`Laboratory investigations are actively
`studying this issue.
`The preliminary safety and high
`therapeutic index of paclitaxel via I-
`
`hour weekly infusion increases thera-
`peutic options for patients with breast
`cancer. Whether as monotherapy or in
`combination,this strategy deserves fur-
`ther exploration in the treatment of
`breast cancer.
`
`References
`
`|
`
`1. Lopes NM, AdamsEF,Pitts TW,et al: Cell
`kill kinetics and cell cycle effects of Taxol on
`human and hamster ovarian cell
`lines. Cancer
`Chemother Pharmacol 32:235-242, 1993.
`2. Licbmann JE, Cook JA, Lipschultz C, et al:
`Cytotoxic studies of paclitaxel in human tumor
`cell lines. Br J Cancer 68:1104-1109, 1993.
`3. Seidman AD, Hochhauser D, Gollub MN,et
`al: Ninety-six hourpaclitaxel infusion after pro-
`gression during short taxane exposure: A phase
`Tl pharmacokinetic and pharmacodynamic study
`I metastatic breast cancer. J Clin Oncol 14:1877-
`1884, 1996,
`4, Chang AY, Boros L, Garrow R, et al:
`Paclitaxel by 3-hour infusion followed by 96-
`hourinfusion onfailure in patients with refracto-
`ry malignant disease. Semin Oncol 22 (suppl 6):
`124-127, 1995.
`5. Gilewski T, Norton L: Cytokinetics and
`breast cancer chemotherapy in Harris JR,
`Lippman ME, Morrow M, Hellman S (eds):
`
`
`
`
`
`Disease of the Breast. Philadelphia, Lippincott-
`Raven, 1996.
`6. Fennelly D, Aghajanian C, ShapiroF,etal:
`Phase I and pharmacologic study of paclitaxel
`administered weekly.
`in patients with relapsed
`ovarian cancer. J Clin Oncol 15:187-192, 1997,
`7. Hainsworth JD, Raefsky EL, Greco FA:
`Paclitaxel administered by a 1-hour infusion: A
`phase I-II trial comparing two schedules. Cancer
`J Sci Am 1:281-287, 1995,
`8. Longnecker SM, Donehower RC,Cates AE,
`et al: High-performance liquid chromatographic
`assay for Taxol in human plasma and urine and
`pharmacokinetics in a phase I trial. Cancer Treat
`Res Rep 71:53-59, 1987.
`9. Huizing MT, Keung ACF, Rosin H,et al:
`Pharmacokinetics of paclitaxel and metabolites
`in a randomized comparative study in platinum-
`pretreated ovarian cancer patients. J Clin Oncol
`11:2127-2135, 1993.
`10. Breter S, Lebedinsku C, Pelayes L, et
`al:’ Phase I/H weekly paclitaxel at 80 mg/m?
`in pretreated patients with breast and ovarian
`cancer. Proc Am Soc Clin Oncol 16:163a, 1997.
`11, Wu-WongJ, Chiou W,HanE,etal: Effects
`of paclitaxel on cell proliferation, apoptosis and
`angiogenesis. Proc Am Assoc Cancer Res 38:
`531, 1997.
`12. Torres KE, Castillo G, Horwitz SB:
`Induction of apoptosis by low concentrations of
`Taxol is not dependent on a G2/M block. Proc
`AmAssoc Cancer Res 38:530, 1997.
`
`ONCOLOGY * VOLUME 12 * NUMBER 1
`
`« S@BPUERTEA=RAIed
`atthe NLM and maybe
`Subject US Copyright Laws.
`
`7
`
`