VOLUME 22
`
`Meeting proceedings ! American Society of Cli
`v. 22 (2003)
`General Collection
`AM785MG
`2003-08-12 11:16713
`
`NA ONAL
`
`PROPERTY OF THE
`NATIONAL
`LIBRARY OF
`MEDICINE
`
`
`
`
`NOVARTIS EXHIBIT 2053
`Breckenridge v. Novartis, IPR 2017-01592
`Page 1 of 4
`
`

`

`Editor: Steven M. Grunberg, MD
`
`Publisher and Managing Editor: Lisa Greaves
`Administrative Assistant: Adell Cokley
`
`Director of Production: Victoria Vaughn
`Production Administrator: Dana Monzi
`
`Executive Editor: Deborah Whippen
`
`The American Society of Clinical Oncology Meeting Proceedings (ISBN 1-932312-02-1) is
`published by the American Society of Clinical Oncology.
`
`Requests for permission to reprint abstracts should be directed to Intellectual Property
`Rights Manager, American Society of Clinical Oncology, 330 John Carlyle St., Suite 300,
`Alexandria, VA 22314. Tel: 703-299-0150; fax 703-518-8157; e-mail permissions@asco.org.
`Editorial correspondence and production questions should be addressed to Managing Editor,
`Meeting Proceedings, American Society of Clinical Oncology, 330 John Carlyle St., Suite 300,
`Alexandria, VA 22314. Tel: 703-299-0150; fax 703-518-8157; e-mail abstracts@asco.org.
`
`Singe issues, both current and back, exist in limited quantities and are offered for sale
`subject to availability. For further information, call 888-273-3508.
`
`Copyright © 2003 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 of 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 or 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 patient.
`
`Abstract management and indexing provided by Database Publishing Group, Inc.,
`Cambridge, MA. Composition services and print production provided by Cadmus Professional
`Services, Linthicum, MD.
`
`Copyright 2003 American Society of Clinical Oncology.
`rn z
`nt: (cid:9)
`
`_
`
`
`
`
`NOVARTIS EXHIBIT 2053
`Breckenridge v. Novartis, IPR 2017-01592
`Page 2 of 4
`
`

`

`Thirty-Ninth
`Annual Meeting of the
`American Society of Clinical Oncology
`May 31-June 3, 2003
`Chicago, Illinois
`Meeting Proceedings
`AS C
`
`IN MEMORIAM
`B.J. Kennedy, MD
`
`The 2003 Meeting Proceedings Is Dedicated
`
`to the Memory of B.J. Kennedy, MD,
`
`ASCO Founding Member and Past President
`
`Copyright 2003 American Society of Clinical Oncology
`
`Thar
`at
`Stt:S:t (cid:9)
`
`Laws
`
`
`
`
`NOVARTIS EXHIBIT 2053
`Breckenridge v. Novartis, IPR 2017-01592
`Page 3 of 4
`
`

`

`200 (cid:9)
`
`Developmental Therapeutics - Molecular Therapeutics (cid:9)
`
`Proceedings of ASCO Volume 22 2003
`
`Poster Discussion, Tue, 8:00 AM - 12:00 PM
`
`800 (cid:9)
`A phase II study of E7070 in patients with metastatic, recurrent, or refractory head
`and neck squamous cell carcinoma (HNSCC): Clinical activity and post-treatment
`modulation of Rb phosphorylation. R. I. Haddad, G. I. Shapiro, L. Weinstein, T.
`Wieczorek, N. Bhattarcharya, M. Loda, J. L. Faucher, H. Raftopoulos, M. Oster,
`M. Posner; Dana-Farber Cancer Institute, Boston, MA; Brigham and Women's
`Hospital, Boston, MA; Columbia University, New York, NY
`
`E7070 is a synthetic sulfonamide that targets the G1 phase of the cell cycle. It
`causes depletion of cyclin E, upregulation of p53 and p21Waf1/Cipl, as well as
`inhibition of cdk2 phosphorylation. All of these events contribute to hypophos-
`phorylation of the retinoblastoma (Rb) protein and cause a blockade in the Gl/S
`transition. We conducted a phase II study of 07070 in patients with noncurable
`HNSCC. Patients received 700 mg/m2 over one hour every 3 weeks. Fifteen
`patients were treated with a median age of 59 years. A total of 39 cycles of
`E7070 were delivered, median 2.6 per patient. Six patients had progressive
`disease (PD) after 2 cycles and 3 patients had PD after one cycle. Five patients
`showed stable disease (SD) after 2 cycles and went on to receive 1 (2 patients), 2
`(2 patients) and 3 additional cycles (1 patients), respectively, before showing
`PD. One patient remains on study and has received 5 cycles with SD. A fine
`needle aspirate (FHA) was obtained from 5 patients prior to treatment and within
`24 hrs after the completion of the first 3-hr infusion to determine whether the
`phosphorylation of Rb was modulated in tumor cells following drug exposure.
`Aspirates were subjected to immunohistochemistry with phospho-specific anti-Rb
`antibodies directed at the T821, 5795 and S807/811 cdk2- and cdk4-specific
`phosphorylation sites.Among the 3 patients with informative samples, results
`were as follows, 07070 demonstrated very limited activity against SCCHN.How-
`
`patient
`
`antibody
`
`1
`
`2
`
`3
`
`Anti-Rb [0821]
`Anti-Rh [0795]
`
`Anti-Rh/pi-821]
`
`Ant-Rb 1p5795)
`Anti-Re
`[0807/811]
`Anti-Rb [pS795]
`Anti-Rb [Total]
`
`% (2+,3+) pre-
`treatment
`32
`86
`
`% (2+,3+) post.
`treatment
`5
`21
`
`13
`
`41
`
`80
`
`to
`70
`
`0
`
`0
`
`0
`
`5
`50
`
`Clinical Outcome
`
`PD after 2 cycles
`
`SD after 2cycles PD
`after 4
`
`SD after 4 cycles. Sall
`on study
`
`ever,our data suggest that cdk activity can be inhibited in tumor cells, resulting
`in a post-treatment modulation of Rb phosphorylation. In the absence of
`cytotoxic activity, more frequent administration of 07070 may be required to
`sustain Rb hypophosphorylation and cytostatic growth arrest.
`
`Poster Discussion, Tue, 8:00 AM - 12:00 PM
`801 (cid:9)
`Phase I study of the proteasome inhihitor hortezomib and pegylated liposomal
`doxorubicin in patients with refractory hematologic malignancies. R. Z.
`Orlowski, P. M. Voorhees, R. Garcia, M. Hall, J. Adams, D. Esseltine, C.
`Dees; Univ of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium
`Pharmaceuticals, Inc., Cambridge, MA
`The proteasome is involved in intracellular protein degradation, and is a
`novel target for therapy of hematologic malignancies. Proteasome inhibi-
`tors also block activation of several survival pathways, including NF-KB and
`p44/42-MAPK, that may limit the effectiveness of anthracyclines, suggest-
`ing such combinations might have enhanced anti-tumor efficacy. We
`sought to evaluate the maximum tolerated dose(MTD), dose limiting
`toxicity(DLT), pharmacokinetics, and pharmacodynamics of the protea-
`some inhibitor bortezomib(B;Velcade) and pegylated, liposomal doxoru-
`bicin(D;Doxil) in patients(pts) with hematologic malignancies. B was given
`as an intravenous bolus at 0.90-1.30-mg/eon days-1, -4, -8, and -11 of
`a 3-week cycle, and Don day-4 at 30-mg/m2. The MTD was defined based
`on cycle-1, while responses were evaluated every 2 cycles. 19 pts have
`been treated, and have included 14 multiple myeloma(MM) pts. A mean of
`4.4 cycles (range 1-10) has been administered, with 15 pts evaluable for
`toxicity. At 0.90-mg/m2 a pt with Crohns disease had grade(g)-3 diarrhea,
`hypotension, confusion and syncope, but no other DLTs were noted at this
`or other levels, and the MTD has yet to be defined. All other non-
`hematologic drug-related toxicities during cycle-1 have been g-1/2 in
`intensity. G-3/4 toxicities in later cycles included fatigue, palmar plantar
`erythrodysesthesia, cytopenias, and neuropathy. Of 10 evaluable MM pts
`complete responses(CR) have been observed in 3, near-CR in 1, partial
`responses(PR) in 3, 1 pt each had a minor response or stable disease, while
`one progressed. Five of these pts, including two of the CRs, had disease
`that previously progressed, or did not respond to anthracycline-based
`therapy, and five are continuing treatment. Also, one pt with relapsed acute
`myeloid leukemia had a PR. Early results from this study suggest that BD
`may be well-tolerated and active in patients with multiple myeloma, and
`possibly other hematologic malignancies. Accrual is continuing to define
`the MID and DLT.
`
`802 (cid:9)
`Poster Discussion, Tue, 8:00 AM - 12:00 PM
`A phase I trial of an oral histone deacetylase inhibitor, MS-275, in advanced
`solid tumor and lymphoma patients. Q. C, Ryan, D. Headlee, A. Sparreboom,
`W. Figg, S. Zhai, J. Trepel, A. Murgo, Y. Elsayed, J. Karp, E, Sausville;
`NatiOnal Cancer lnstitue, Bethesda, MD; Cancer Institute of New Jessy,
`New Brunswick, NJ; The Sidney Kimmel Cancer Center at Johns Hopkins,
`Baltimore, MD
`We are conducting a Phase I trial using MS-275, an orally administered,
`synthetic histone deacetylase inhibitor, in advanced solid tumor and
`lymphoma patients. The trial initially used a daily x 28, repeated every six
`weeks, dosing schedule with an accelerated titration design, beginning at 2
`mg/m2 (i.e., 1/10 of rat maximal tolerated dose (MID)). However, in
`humans the MTD was exceeded at the 1st dose level, with grade 3 AST,
`hyposphosphatemia, hypoalbuminemia, pleural effusion and epigastric
`pain. Preliminary evidence of a substantially longer half-life of MS-275 in
`humans as compared to preclinical species likely accounts for this finding.
`A once q14 day schedule was then implemented, also starting at 2 mg/m2
`but escalating with 2 mg/m2 increments. To date, 20 patients have been
`treated on this schedule. Although escalated to level 5 (10 mg/m2 q 2 wk),
`the MTD has not yet been reached. Frequent grade 1-2 toxicities include
`fatigue (50%); nausea (50%); hypoalbuminemia (35%), headache (35%),
`anxiety (30 %), dyspepsia (30%), vomiting (30%); dysgeusia (20%),
`anemia (20%), fever (20%), and hyponatremia (20%). Besides the first
`course toxicities, hypoalbuminemia and progressive fatigue as a continuing
`effect of MS-275 occurred, especially at higher dose levels, and are of
`concern for long term dosing. Peak plasma concentrations were observed at
`6 - 24 h after dosing, suggesting slow absorption, and in the range of 10 -
`50 ng/ml. This concentration is within the range that might affect
`proliferation of certain cell types preclinically. Dose dependence of
`exposure to MS-275 occurred, but no further increase in area under the
`curve at doses above 6 mg/m2 was evident. This phenomenon likely
`involves nonlinear, apparent saturable absorption processess. Increased
`histone H3 acetylation in peripheral blood mononuclear cells was apparent
`at all dose levels, by immunofluorescent analysis. Based on these data, a
`new oral schedule, weekly x4, repeated every six weeks, as well as an
`intravenous formulation are being developed,
`
`Poster Discussion, Tue, 8:00 AM - 12:00 PM
`803 (cid:9)
`A phase I study of the oral mTOR inhibitor RAD001 as monotherapy to identify
`the optimal biologically effective dose using toxicity, pharmacokinetic (PK)
`and pharmacodynamic (PD) endpoints in patients with solid tumours. A.
`O'Donnell, S. Faivre, 1. Judson, C. Delbado, C. Brock, H. Lane, N. Shand,
`K. Hazell, J.-P. Armand, E. Raymond; Royal Marsden Hospital, Sutton, UK;
`Institute Gustave Roussy, Villejuif, France; Novartis Pharma AG, Basel,
`Switzerland
`RAD001, a novel derivative of rapamycin, interacts with the mTOR protein
`kinase to inhibit downstream signalling proteins crucial to cell cycle
`progression. Pre-clinical in vitro and in vivo studies have shown dose
`dependent inhibition of tumour growth and reduced tumour vascularity, as
`well as the ability to potentiate the activity of a number of cytotoxics
`including paclitaxel and gemcitabine. Methods: This phase I dose escala-
`tion study was performed to identify the optimal biologically effective dose
`based on toxicity, PK and PD assessments using the biomarker p70 S6
`kinase 1 (S6K1) activity in peripheral blood mononuclear cells (PBMCs).
`Indication of activity was also sought using conventional and PET imaging.
`Treatment with RAD001 was given orally, once weekly. Results: Cohorts of
`4 patients were treated at each of 4 dose levels: 5, 10, 20 and 30ing.
`(7M:9F; Median age 60y, Range 32-75 y) RAD001 was well tolerated with
`only mild degrees (Gr 1/2) of anorexia, fatigue, rash, mucositis, headache,
`hyperlipidemia and gastrointestinal disturbance. PK results are consistent
`with prior experience (renal transplant and healthy subject studies): AUC
`increasing in proportion to dose, a plateau in Cmax occurring at doses
`.20mg and a terminal tli, of 26-38 hours. 4 patients (hepatocellular
`10mg; fibrosarcoma 10mg; NSCLC x 2, 30rng) have stable disease >16
`weeks. A responding patient with NSCLC showed e reduction in 18FDG
`uptake on PET scanning after week 3. S6K1 activity in PBMCs was
`inhibited for 3-5 days at 5 and 10 mg dose levels. At doses .?-20mg 7/8
`patients exhibited inhibition for at least 7 days. Conclusions: Weekly
`administration of 20mg RAD001 in patients, gives plasma concentrations
`and sustained S6K1 inhibition equivalent to the PK levels and PD changes
`that correlate with anti-tumour effects in rodents treated with this sched-
`ule. Doses above 20mg result in only marginally increased inhibition.
`Combination studies have been initiated and we continue to explore the PD
`impact of mTOR inhibition in human tumours.
`
`This mate ria I was teeied
`
`
`
`
`NOVARTIS EXHIBIT 2053
`Breckenridge v. Novartis, IPR 2017-01592
`Page 4 of 4
`
`