Bie (one)wy
`
`Meeting proceedings / American Society of Cli
`v. 22 (2003)
`Genera! Collection
`W1 AM785MG
`2003-08-12 11:16:13
`
`MEETING
`
`INGA
`SOCIETY OF
`CLINICAL
`ONCOLOGY
`
`Page 001
`
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`MEDICINE
`
`West-Ward Pharm.
`Exhibit 1029
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`Page 001
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`

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`

`

`Thirty-Ninth
`Annual Meeting of the
`AmericanSociety of Clinical Oncology
`May31-June 3, 2003
`Chicago, Illinois
`Meeting Proceedings
`
`ASCE
`
`The 2003 Meeting Proceedings Is Dedicated
`
`to the Memory of B.J. Kennedy, MD,
`
`
`
`
`
`IN MEMORIAM
`B.J. Kennedy, MD
`
`
`
`
`
`ASCO Founding Member and Past President
`
`Copyright 2003 American Society of Clinical Oncology
`
`This material was copied
`atthe NLMand maybe
`Subject US Copyright Loews
`
`West-Ward Pharm.
`Exhibit 1029
`Page 003
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`Exhibit 1029
`Page 003
`
`

`

`200
`
`Developmental Therapeutics - Molecular Therapeutics
`
`Proceedings of ASCO Volume 22 2003
`
`801
`
`Poster Discussion, Tue, 8:00 AM - 12:00 PM
`
`Poster Discussion, Tue, 8:00 AM - 12:00 PM
`800
`A phaseIl study of E7070in patients with metastatic, recurrent, or refractory head
`Phase | study of the proteasome inhibitor bortezomib and pegylated liposomal
`and neck squamous cell carcinoma (HNSCC): Clinical activity and post-treatment
`doxorubicin in patients with refractory hematologic malignancies. R. 2.
`modulation of Rb phosphorylation. R.
`|, Haddad, G.
`|. Shapiro, L. Weinstein, T.
`Orlowski, P. M. Voorhees, R. Garcia, M. Hall, J. Adams, D. Esseltine, C.
`Wieczorek, N. Bhattarcharya, M. Loda, J. L. Faucher, H. Raftopoulos, M. Oster,
`Dees; Univ of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium
`M. Posner; Dana-Farber Cancer Institute, Boston, MA; Brigham and Women’s
`Pharmaceuticals, Inc., Cambridge, MA
`Hospital, Boston, MA; Columbia University, New York, NY
`£7070 is a synthetic sulfonamide that targets the G1 phase of the cell cycle. It
`The proteasomeis involved in intracellular protein degradation, and is a
`causes depletion of cyclin E, upregulation of p53 and p2]Waf1/Cip1, as well as
`novel target for therapy of hematologic malignancies. Proteasome inhibi-
`inhibition of cdk2 phosphorylation. All of these events contribute to hypophos-
`tors also block activation of several survival pathways, including NF-KB and
`phorylation of the retinoblastoma (Rb) protein and cause a blockade in the GI/S
`p44/42-MAPK, that maylimit the effectiveness of anthracyclines, suggest-
`transition. We conducted a phase || study of E7070 in patients with noncurable
`HNSCC. Patients received 700 mg/m2 over one hour every 3 weeks. Fifteen
`ing such combinations might have enhanced anti-tumor efficacy. We
`patients were treated with a median age of 59 years. A total of 39 cycles of
`sought
`to evaluate the maximum tolerated dose(MTD), dose limiting
`£7070 were delivered, median 2.6 per patient. Six patients had_progressive
`toxicity(DLT), pharmacokinetics, and pharmacodynamics of the protea-
`disease (PD) after 2 cycles and 3 patients had PD after one cycle. Five patients
`some inhibitor bortezomib(B;Velcade) and pegylated,
`liposomal doxoru-
`showed stable disease (SD) after 2 cycles and wenton to receive 1 (2 patients), 2
`bicin(D;Doxil) in patients(pts) with hematologic malignancies. B was given
`(2 patients) and 3 additional cycles (1 patients), respectively, before showing
`as an intravenous bolus at 0.90-1.30-mg/m? on days-1, -4, -8, and -11 of
`PD. One patient remains on study and has received 5 cycles with SD.Afine
`needle aspirate (FNA) was obtained from 5 patients prior to treatment and within
`a 3-week cycle, and D on day-4 at 30-mg/m?. The MTD was defined based
`24 hrs after the completion of the first 3-hr infusion to determine whether the
`on cycle-1, while responses were evaluated every 2 cycles. 19 pts have
`phosphorylation of Rb was modulated in tumor cells following drug exposure.
`been treated, and have included 14 multiple myeloma(MM) pts. A mean of
`Aspirates were subjected to immunchistochemistry with phospho-specific anti-Rb
`antibodies directed at the T821, $795 and $807/811 cdk2- and cdk4-specific
`4.4 cycles (range 1-10) has been administered, with 15 pts evaluable for
`phosphorylation sites.Among the 3 patients with informative samples, results
`toxicity. At 0.90-mg/m? a pt with Crohns disease had grade(g)-3 diarrhea,
`were as follows: E7070 demonstrated very limited activity against SCCHN.How-
`hypotension, confusion and syncope, but no other DLTs were notedatthis
`% (2+,3+) pre-
`% (2+,3+) post-
`or other
`levels, and the MTD has yet
`to be defined. All other non-
` patient antibody treatment treatment Clinical Outcome
`
`
`
`
`hematologic drug-related toxicities during cycle-1 have been g-1/2 in
`1
`Anti-Ro [pT821]
`32
`5
`PD after 2 cycles
`intensity. G-3/4 toxicities in later cycles included fatigue, palmar plantar
`Anti-Ro [pS795]
`86
`21
`erythrodysesthesia, cytopenias, and neuropathy. Of 10 evaluable MM pts
`.
`complete responses(CR) have been observed in 3, near-CR in 1, partial!
`Anti-Rb {pT821]
`13
`0
`responses(PR) in 3, 1 pt each had a minor response orstable disease, while
`Aati-Rb [pS795]
`M
`0
`one progressed, Five of these pts, including two of the CRs, had disease
`Anti-Rb
`80
`0
`that previously progressed, or did not respond to anthracycline-based
`[p$807/811]
`Anfi-Rb [9$795}
`80
`5
`therapy, and five are continuing treatment.Also, one pt with relapsed acute
`Anti-Rb
`[Total
`70
`50
`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 MTD and DLT.
`
`2
`
`3
`
`.
`
`SD after 2cycles PD
`after 4
`
`SD after 4 cycles. Stil!
`on study
`
`ever,our data suggest that cdk activity can be inhibited in tumorcells, resulting
`in a post-treatment modulation of Rb phosphorylation.
`In the absence of
`cytotoxic activity, more frequent administration of E7070 may be required to
`sustain Rb hypophosphorylation and cytostatic growth arrest.
`
`Poster Discussion, Tue, 8:00 AM ~ 12:00 PM
`802
`A phaseI trial of an oral histone deacetylase inhibitor, MS-275, in advanced
`solid tumor and lymphomapatients. Q. C. Ryan, D. Headiee, A. Sparreboom,
`W. Figg, S. Zhai, J. Trepel, A. Murgo, Y. Elsayed, J. Karp, E. Sausville;
`National Cancer Institue, 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 | trial using MS-275, an orally administered,
`synthetic histone deacetylase inhibitor,
`in advanced solid tumor and
`lymphomapatients. 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 {MTD}). However,
`in
`humans the MTD was exceeded at the lst 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 accountsforthis 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%). Besidesthe 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 preciinically. Dose dependence of
`exposure to MS-275 occurred, but no further increase in area under the
`curve at doses above 6 mg/m2 wasevident. 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.
`
`1
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`
`PosterDiscussion, Tue, 8:00 AM - 12:00 PM
`803
`A phase | study of the oral mTOR inhibitor RADOO1 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
`
`RADOO1, 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
`dependentinhibition 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 | dose escala-
`tion study was performed to identify the optima! 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 RADOO1 wasgiven orally, once weekly. Results: Cohorts of
`4 patients were treated at each of 4 dose levels: 5, 10, 20 and 30mg.
`(7M:9F; Median age 6Oy, Range 32-75 y) RADOO 1 waswell 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 ty). of 26——38 hours. 4 patients (hepatocellular
`10mg; fibrosarcoma 10mg; NSCLC x 2, 30mg) have stable disease >16
`weeks, A responding patient with NSCLC showed a reduction in 'SFDG
`uptake on PET scanning after week 3. S6K1 activity in PBMCs was
`inhibited for 3—5 days at 5 and 10 mg doselevels. At doses =20mg 7/8
`patients exhibited inhibition for at
`least 7 days. Conclusions: Weekly
`administration of 20mg RADOO1 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 MTORinhibition in human tumours.
`
`This materia was comed
`
`West-Ward Pharm.
`Exhibit 1029
`Page 004
`
`West-Ward Pharm.
`Exhibit 1029
`Page 004
`
`