Drugs i11 R&D.
`DUP - General Collection
`W1 DR893TC
`v. 5,no.6
`2004
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`TM
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`2004, Vol. 5, No. 6 (pp. 313-369)
`ISSN: 1174-5886
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`\
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`Research Perspectives
`Antineoplaston AlO and AS2-1
`D-003
`\ Nonsteroidal Anti-Inflammatory Drugs
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`PROPERTY OF THE
`NATIOI'\JAL
`LIBRARY OF
`MEDICINE
`
`.·-._ ________________ _;>
`
`\ \
`La_~.
`a 1S
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`INTERNATIONAL
`
`Ex. 1115-0001
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`

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`Vol. 5, No. 6, 2004
`.. ·-,. ___ ;_, .... ·.~,, __ "----·----·--·-·
`
`.
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`.
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`Dru s
`inR&Dg
`
`Contents
`
`Acknowledgement
`
`Original Research
`Article
`
`Short
`Communication
`
`Phase II Study of Antineoplaston AlO and AS2-1 in
`Children with Recurrent and Progressive Multicentric
`Glioma: A Preliminary Report
`SR BurzyHski, RA Weaver, RI Lewy, TJ JaHicki, CF Jurida,
`BG Szymkowski, MI Kha11, M Bestak
`
`In Vitro Effects of Selective and Non-Selective
`Nonsteroidal Anti-Inflammatory Drugs on the Frequency
`of Sister Chromatid Exchanges
`S Oztiirk, BG Koseoglu, H Kor;ak, S Palmzduz, K (:efle, H Erkal
`Effect of 0-003 on a Subconvulsive Dose of Kainic Acid in
`Rats
`D Carbajal, M Noa, V Molina, R Mas, M de L Arruzazabala
`
`Adis R&D Profile
`
`Gadofosveset: MS 325, MS 32520, Vasovist, ZK 236018
`
`Icatibant: HOE 140, JE 049, JE049
`
`Omeprazole/ Antacid-Powder Suspension - Santarus:
`Omeprazole/Sodium Bicarbonate Powder - Santarus,
`SANOS
`Palifermin: AMJ 9701, KGF - Amgen, Recombinant
`Human Keratinocyte Growth Factor, rHu-KGF
`Safinamide: FCE 26743, NW 1015, PNU 151774,
`PNU 151774E
`Tamibarotene: AM 80, Retinobenzoic Acid, Tamibaro
`
`Temsirolimus: CCI 779, CCI-779, Cell Cycle Inhibitor-779
`
`Testosterone Undecanoate - Schering AG
`
`313-314
`
`315-326
`
`327-330
`
`331-336
`
`339-342
`
`343-348
`
`349-350
`
`351-354
`
`355-358
`
`359-362
`
`363-367
`
`368-369
`
`Register for the free Adis Electronic Table of Contents E-Mail Alert Service today at www.adisonline.info
`Drugs in R&D is indexed in Index Medicus/MEDLINE, EMBASE, the Chemical Abstracts Service (CAS) and International
`Pharmaceutical Abstracts (IPA). Individual articles are available through the ADONIS document delivery system and are available
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`
`Ex. 1115-0002
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`t.a~ .
`a 1S
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`INTERNATIONAL
`
`International Editorial Board
`
`G. Amsden, Cooperstown, NY, USA
`
`S.E. Bellibas, Nutley, NJ, USA
`
`E. Beghl, Milan, Italy
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`S. Bloomfield, Cincinnati, OH, USA
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`A. Bryskler, Paris, France
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`E. Christophers, Kiel, Germany
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`M.J. Eadie, Brisbane, QLD, Australia
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`D. Furst, Seattle, WA, USA
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`LC. Groop, Malmo, Sweden
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`F. Horak, Vienna, Austria
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`B.D. Kahan, Houston, TX, USA
`R. Kowomorl, Tokyo, Japan
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`M.G. Kris, New York, USA
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`M. Loder, London, UK
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`K. McCormack, Leighton Buzzard, UK
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`J. Hamilton-Miller, London, UK
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`T. Morgan, Melbourne, VIC, Australia
`G. Morris Ill, Milwaukee, WI, USA
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`G. Moyle, London, UK
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`P. Nathan, Melbourne, VIC, Australia
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`D.J. Nutt, Bristol, UK
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`E. Perucca, Pavia, Italy
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`S.C. Schachter, Boston, MA, USA
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`M.A. Smith, Cleveland, OH, USA
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`F. Vajda, Melbourne, VIC, Australia
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`C.J. van Boxtel, Amsterdam,
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`The Netherlands
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`H. van Leusden, Oosterbeek,
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`The Netherlands
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`J. Wilson, Shreveport, LA, USA
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`V. Wong, Hong Kong
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`N. Yuen, Apex, NC, USA
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`Dru s
`i"R&Dg
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`Alm and Scope: The aim of Drugs in R&D is to provide timely information on:
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`ADIS R&D PROFILE
`
`Drugs R D 2004: 5 (6): 363-367
`1174-5886/04/0006-0363/$31.00/0
`
`(D 2004 Adis Data !nformatlon BV, Alf rights reserved.
`
`Temsirolimus
`CCI 779, CCI-779, Cell Cycle Inhibitor-779
`
`Abstract
`
`Wyeth (formerly American Home Products) is developing temsirolimus [Cell
`cycle inhibitor-779, CCI 779], an ester analogue of sirolimus, for the treatment of
`cancer, multiple sclerosis and rheumatoid arthritis. Temsirolimus binds to the
`cytosolic protein, FKBP, which subsequently inhibits mTOR (mammalian target
`of rapamycin). Inhibition of mTOR blocks a number of signal transduction
`pathways that suppress translation of several key proteins regulating the cell
`cycle. These effects lead to a cell cycle block at the G1 phase.
`In animal models of human cancers, temsirolimus inhibited the growth of a
`diverse range of cancer types even when an intermittent dosing schedule was
`used. The compound also appears to have potential for the blockade of inflam(cid:173)
`matory responses associated with autoimmune and rheumatic diseases by inhib(cid:173)
`iting T-cell proliferation.
`On I 1 March 2002, American Home Products changed its name and the name
`of its subsidiary Wyeth-Ayerst to Wyeth.
`During the first half of 2004, Wyeth initiated ongoing recruitment into a US
`phase III trial comparing orally administered temsirolimus plus letrozole versus
`letrozole alone as first-line treatment among sel200 postmenopausal women with
`advanced breast cancer. The multicentre, randomised, double-blind, placebo(cid:173)
`controlled trial is estimated to last 34 months. All subjects will have the option of
`participating in the long-term follow-up phase of the trial that involves follow-up
`every 3 months until disease progression; the primary endpoint is overall progres(cid:173)
`sion-free survival.
`In August 2004, the US FDA granted temsirolimus fast-track status for the
`first-line treatment of poor-prognosis patients with advanced renal cell carcino(cid:173)
`ma.fll
`Previously in March 2002, temsirolimus received fast-track status from the
`FDA for the treatment of renal cell carcinoma in patients who failed to respond to
`interleukin-2 treatment. Wyeth intends to file a NDA for temsirolimus for this
`indication by 2006.121
`Researchers from Wyeth presented the findings from a preclinical study of
`temsirolimus at the 67th Annual Scientific Meeting of the American College of
`Rheumatology and the 38th Annual Meeting Association ofRheumatology Health
`Professionals (ACR/ARHP-2003) [Orlando, FL, USA; October 2003]. The aim of
`this study was to determine the effect oftemsirolimus on lymphocyte proliferation
`and cytokine production. Since lymphocytes and cytokines are significantly
`involved in the pathogenesis of rheumatoid arthritis, temsiro!imus could have
`
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`364
`
`Table I. Features and properties
`
`Chemical name
`
`Molecular formula
`CAS number
`WHO ATC code
`
`EphMRA ATC code
`
`Originator
`Highest development phase
`
`Properties
`Mechanism of action
`Pharmacodynamics
`
`Route
`Adverse events
`
`1. Profile
`
`disease-modifying antirheurnatic drug (DMARD) activity against rheumatoid
`arthritis via the inhibition of these factors_l3l
`According to Wyeth's investor presentation in June 2004, the patent covering
`ternsirolimus is due for expiry in 2014.
`
`[1 R,9S, 12S[1" R,3" R,4"
`R], 15R, 18R, 19R,21 R,23S,30S,32S,35R]-1, 18-Dihydroxy-12-[2-[4-[3-hydroxy-2-(hyi
`cyclohexyll-1-methylethyll-19,30-dimethoxy-15, 17,21,23,29,35-hexamethyl-11,36-d
`[30.3.1.0(4,9)]hexatriaconta-16(E),24(E),26(E),28(E)-
`tetraene-2,3, 10, 14,20-pentaone
`C56 H87 N 016
`162635-04-3
`L04A-A (Selective immunosuppressive agents)
`M01 (Antiinflammatory and Antirheumatic Products)
`L01 D-C (Other cytotoxic antibiotics)
`N07X (Other Nervous System Drugs)
`M1 A (Anti-Rheumatics, Non-Steroidal)
`N7 (Other CNS Drugs)
`L 1 D (Anti neoplastic Antibiotics)
`L4A (lmmunosuppressive Agents)
`Wyeth: USA
`Phase II (USA)
`
`Interferon y antagonists
`Cytotoxicity in human brain tumour cell lines; tumour growth delay in
`medulloblastoma and glioblastoma xenografts; reversibly inhibits lymphocyte
`activation and cytokine production in vitro
`IV-infusion
`Most Frequent: Drug hypersensitivity, Mucositis, Skin disorders; Occasional:
`Asthenia, Pruritus; Rare: Diarrhoea, Hypocalcaemia, Vomiting
`
`l. l Pharmacokinetics
`
`Temsirolimus' pharmacokinetic parameters fol(cid:173)
`lowing weekly treatment have been examined in
`various studies including a phase I dose-escalation
`study among 24 patients with cancer at doses from
`7.5 to 220 mg/m2 and among 16 patients with ad(cid:173)
`vanced renal cancer in doses of 25, 75 and 250mg.
`With increasing dose (25 to 250 mg/m2), tem(cid:173)
`sirolimus exposure in whole blood increased with
`Cmax ranging from 595 to 2830 ng/mL and AUC
`from 1580 to 2700 ng • h/mL. Temsirolimus distri(cid:173)
`bution exceeded total body water and increased with
`
`dose, while V dss ranged from 232 to 897L. CL of
`temsirolimus also increased with dose from 16.1 to
`98.0 L/h. Sirolimus, a major metabolite of tem(cid:173)
`sirolimus, exhibited exposures typically exceeding
`that of the parent drug. Mean tit, for temsirolimus
`was 13h and for sirolimus this ranged from 40 to
`57h. Data from dose escalation indicated that no
`advantage in exposure or its variability was gained
`by using body surface area-normalised dosing,
`therefore flat dosing was adopted for further clinical
`development. In addition, no age or gender differ(cid:173)
`ences in exposure have been observed to date_l4,51
`
`Among the 45 patients with solid tumours receiv(cid:173)
`ing temsirolimus 0.75-19.1 mg/m2/day by IV info-
`
`'CJ 2004 Adls Data Information BV. All rights reserved.
`
`Drugs RD 2004; 5 (6)
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`Temsirolimus
`
`365
`
`sion, 17 were assessed for pharmacokinetic analysis.
`Little or no accumulation of temsirolimus occurred
`over the treatment courses. There was a dose-depen(cid:173)
`dent increase in AUC values and the median t 11, was
`15.2h. Patients received temsiro-limus for 5 consec(cid:173)
`utive days every 2 weeks for a median of four
`courses.1 61
`Pharmacokinetics were linear at doses of tem(cid:173)
`sirolimus::;; 3.12 mg/m2/day in 17 evaluable patients
`with solid tumours_l7l
`
`1.2 Adverse Events
`
`Interim results from an ongoing phase I trial in
`cancer patients indicated that weekly temsirolimus
`was generally well tolerated. No dose-limiting or
`grade 3-4 toxicities were observed. Among the first
`12 patients, the most common adverse events were
`mild skin reactions and inflammation of the mucous
`membranes, which occurred at all dose levels. The
`intensity of these events was independent of dose or
`treatment duration. Mild hypersensitivity reactions
`
`Table II. Drug development history
`
`occurred in all 12 patients, mucositis in seven, and
`skin dryness, itching, scaling and factial erythema in
`six. Five patients experienced reactivation of peri(cid:173)
`oral herpes lesions. Temsirolimus 7.5-60 mg/m2/
`day was given by weekly IV infusion.18,91 Updated
`results from this trial showed that five of nine male
`patients had reduced testosterone levels after receiv(cid:173)
`ing doses of temsirolimus ?.7.5 mg/m2/week.
`Changes in libido were reported by most of the
`affected patientsP 01
`
`When temsirolimus was administered five times
`daily every 2 weeks at doses of ::;;I 9.1 mg/m2/day,
`dose-limiting toxicities included grade 3 hypocal(cid:173)
`caemia, transaminase elevation as well as vomiting
`and grade 2 diarrhoea as well as asthenia, which
`occurred
`in
`three of 51 patients with solid
`tumours.171
`
`In a phase II study in patients with metastatic
`renal cancer, weekly temsirolimus was associated
`with maculopapular
`rash
`(76% of patients),
`mucositis (70%) and asthenia (50%). Grade 3-4
`
`Apr 1999
`Aug 1999
`Oct 2001
`Feb 2002
`Mar 2002
`
`Mar 2002
`
`Mar 2003
`May 2003
`Oct 2003
`Dec 2003
`Dec 2003
`Apr 2004
`May 2004
`May 2004
`Jun 2004
`Jun 2004
`Jul 2004
`Aug 2004
`
`Preclinical development for Cancer in the US (IV-infusion)
`Phase-I for Cancer in the US (IV-infusion)
`Phase-II for Cancer in the US (IV-infusion)
`Phase-II in Breast cancer in the US (PO)
`Temsirolimus has received fast-track status for the treatment of renal cell
`carcinoma among patients who have failed to respond to interleukin-2 treatment
`in the US
`American Home Products and its subsidiaries Wyeth-Ayers! and Wyeth Lederle
`are both now called Wyeth
`Prein Multiple sclerosis in the US (IV-infusion)
`Phase-II in Multiple sclerosis in the US {IV-infusion)
`Prein Rheumatoid arthritis in the US (unspecified route)
`Phase-II in Non-Hodgkin's lymphoma in the US (IV-infusion)
`Phase-II in Rheumatoid arthritis in the US (unspecified route)
`Phase-Ill in Renal cancer in the US {IV-infusion)
`Phase-II in Colorectal cancer in the US {IV-infusion)
`Phase-II in Non-small cell lung cancer in the US {IV-infusion)
`Phase-Ill in Breast cancer in the US (PO)
`Phase-Ill in Non-Hodgkin's lymphoma in the US {IV-infusion)
`Wyeth has initiated enrolment in a phase Ill trial for Breast cancer in the US
`Temsirolimus has received fast-track status for first-line treatment of renal cell
`carcinoma in patients with poor prognosis in the US
`
`r0 2004 Adis Doto Information BV. All rights reserved.
`
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`366
`
`( 17% ), hy(cid:173)
`included hyperglycaemia
`events
`pophosphataemia (13%), anaemia (9%) and hyper(cid:173)
`triglyceridaemia (6%). The proportion of patients
`who discontinued because of toxicity was 14, 18 and
`24% at the 25, 75 and 250mg dose levels, respec(cid:173)
`tively.[5l
`In a phase II trial (n = 106), weekly temsirolimus
`was generally well tolerated in pretreated patients
`with advanced breast cancer. Grade 3-4 events in
`patients treated at a dose of 250mg versus 75mg
`included mucositis (14 vs 6%), leucopenia (6 vs
`9%), depression (10 vs 0%), somnolence (10 vs 2%)
`and hyperglycaemia (8 vs 6%).[Jll
`
`1.3 Pharmacodynamics
`
`1.3. 1 Cancer
`Preclinical studies: Temsirolimus had ICso val(cid:173)
`ues of <10 ng/mL in four of seven medulloblastoma
`and one of two neuroblastoma cell lines tested. In
`contrast, the ICso in the glioblastoma cell line,
`U25 l, was > 1000 ng/mL. In athymic mice bearing
`DAOY medulloblastoma flank xenografts, tem(cid:173)
`sirolimus IP five times daily for 1 or 2 weeks,
`delayed tumour growth to five times the original
`volume, by 160% and 240%, respectively, com(cid:173)
`pared with controls. Prolonged growth delay was
`observed in 20% of mice treated for 2 weeks, but
`there was no prolongation of tumour growth delay in
`mice treated for 1 week. Re-treatment of large
`tumours with temsirolimus restored growth inhibi(cid:173)
`tion but did not result in tumour regression.l12l
`In nude mouse xenografts of staged human
`glioblastoma (U87MG) tumours, tumour growth
`was blocked by a variety of treatment regimens, the
`minimum effective dose being 0.1-1.0 mg/kg. Tu(cid:173)
`mour-bearing mice treated with temsirolimus for 5
`consecutive days still experienced tumour growth
`inhibition 14 days later. In contrast, the effect of
`temsirolimus on immune function had disappeared
`1 day after drug withdrawaU13l
`
`Temsirolimus reduced runaway growth and en(cid:173)
`largement in some areas of the brain in young mice
`that lacked PTEN. In some areas of the adult mouse
`brain, temsirolimus reversed abnormal growth. In
`addition, temsirolimus reduced the frequency of
`seizures and the death rate in adult mice that did not
`have cancer but suffered neurological deficits
`caused by abnormal growth of brain cells in the
`absence of PTEN.[141
`Temsirolimus inhibited the growth of six of eight
`human breast cancer cell lines i11 vitro, with an ICso
`s50 nmol/L. The temsirolimus-sensitive cell lines
`either did not express the tumour suppressor PTEN,
`or were estrogen dependent, and/or they overex(cid:173)
`pressed the Her-2/neu oncogene. MDA-MB-435
`and MDA-MB-231,
`the
`resistant cell
`lines
`(ICso > 1.0 µmol/L), exhibited none of these charac(cid:173)
`teristics. In an in vivo study carried out in nu/nu
`mice with xenografts, MDA-MB-468 was still sen(cid:173)
`sitive to the effects of temsirolimus. Regression of
`the tumours was observed at the higher doses
`(40 mg/kg), and delayed tumour growth was seen at
`the lower doses (10 mg/kg). The resistant cell line
`MDA-MB-435 showed no growth inhibition.l 15l
`
`1.3.2 Rheumatic Disease
`Preclinical studies: Temsirolimus inhibited lym(cid:173)
`phocyte activation and cytokine production with an
`ICso in the subnanomolar to nanomolar range.
`Through this mechanism, temsirolimus has the po(cid:173)
`tential to suppress the inflammatory responses in(cid:173)
`volved in rheumatoid arthritis. Temsirolimus inhib(cid:173)
`ited proliferation of human peripheral blood
`mononuclear cells (PBMCs) with an ICso of
`0.5 nmol/L. Concentrations as low as 0.1 ng/mL of
`temsirolimus inhibited the proliferation of murine
`T cells. This inhibition could be reduced with in(cid:173)
`creasing concentrations of the anti-T-cell receptor
`(TCR) stimulus. Production of interleukin-2, in(cid:173)
`terleukin-4 and interferon y by the mouse T cells
`was also
`inhibited by concentrations of tem(cid:173)
`sirolimus as low as 0.1 ng/mL. This inhibition ap-
`
`<0 2004 Adls Data Information BV. All rights reserved.
`
`Drugs R D 2004; 5 (6)
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`Temsirolimus
`
`367
`
`peared to be independent of the concentration of the
`anti-TCR stimulus. Inhibition of both proliferation
`and cytokine production by temsirolimus was re(cid:173)
`versible by delivery of a co-stimulatory signal
`through CD28J3l
`
`1.4 Therapeutic Trials
`
`1.4. 1 Cancer
`Breast cancer: In a phase II trial (n = 106),
`temsirolimus was associated with response or stable
`disease for 2::8 weeks in 49% of pretreated patients
`with advanced breast cancer. The objective response
`rate was 8%, although several unconfirmed re(cid:173)
`sponses were included in the stable disease rate.l 11 l
`
`Modest activity was observed with temsirolimus
`administered five times daily every 2 weeks to pa(cid:173)
`tients with solid tumours. Dose escalation from 0.75
`to 19.1 mg/m2/day was performed in 51 patients.
`One patient with non-small cell lung cancer had a
`partial response, and minor response or stable dis(cid:173)
`ease for >4 months was observed in eight other
`patients.!7l
`
`References
`I. Wyeth Pharmaceuticals. FDA Grants Fast Track Status to Tem(cid:173)
`sirolimus, an Investigational Drug for First-Line Treatment of
`Patients With Advanced Renal Cell Carcinoma. Media Re(cid:173)
`lease: 17 Aug 2004. Available from URL: http://www.wy(cid:173)
`eth.com
`
`2. Wyeth. Wyeth Discusses R&D Strategy and Details Robust
`Pipeline At Investor Conference. Media Release: 2 Jun 2004.
`Available from URL: http://www.wyeth.com
`
`3. Nickerson-Nutter CL, O'13rien C, Zhang Y, et al. CCI-779
`inhibits lymphocyte proliferation and cytokine production, and
`is a potential therapeutic agent for treatment of rheumatoid
`arthritis. Arthritis and Rheumatism 48 (Suppl.): 465, No. 9,
`Sep 2003
`
`4. Raymond E, Alexandre J, Faivre S, et al. Safety and
`pharmacokinetics of escalated doses of weekly intravenous
`infusion ofCCI-779, a novel mTOR inhibitor, in patients with
`cancer. Journal of Clinical Oncology 22: 2336-2347, No. 12,
`15 Jun 2004
`
`5. Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II
`study of multiple dose levels of CCI-779, a novel mammalian
`target of rapamycin kinase inhibitor, in patients with advanced
`refractory renal cell carcinoma. Journal of Clinical Oncology
`22: 909-918, No. 5, 1 Mar 2004
`
`6. Hidalgo M, Rowinsky E, Erlichman C, ct al. CCI-779, a
`rapamycin analog and multifaceted inhibitor of signal trans(cid:173)
`duction: a phase I study. 36th Annual Meeting of the Amaican
`Society of Clinical Oncology 19: 187 (plus poster), 20 May
`2000
`
`7. Hidalgo M, Rowinsky E, Erlichman C, et al. A phase I and
`pharmacological study of CCI-779, a rapamycin ester cell
`cycle inhibitor. Annals of Oncology 11 (Suppl. 4): 133 (plus
`oral presentation), 2000
`
`8. Cooney Waters Group. Novel anti-cancer agent shows minimal
`side effocts with preliminary evidence of tumor shrinkage:
`research results presented at International Conference spon(cid:173)
`sored jointly by AACR, NCI and EORTC. Media Release [2
`pages], 16 Nov 1999
`
`9. Alexandre J, Raymond E, Depenbrock H, ct al. CCI-779, a new
`rapamycin analog, has antitumor activity at doses inducing
`only mild cutaneous effects and mucositis: early results of an
`ongoing phase I study. Clinical Cancer Research 5 (Suppl.):
`3730, Nov 1999
`
`10. Raymond E, Alexandre J, Depenbrock H, et al. CCI-779, a
`rapamycin analog with antitumor activity: a phase I study
`utilizing a weekly schedule. 36th Annual Meeting of the Amer(cid:173)
`ican Society of Clinical Oncology 19: 187 (plus poster), 20
`May 2000
`
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`@ 2004 Adls Data Information BV. Ail rights reserved.
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