November 20, 2001
`
`HEALTH SCIENCES
`
`LIBRARIES
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`VOLUME 98
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`,
`
`NUMBER 11
`NOVEMBER 16. 2001
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`PART 1 OF 2 PARTS
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`
`
`
`American Society of
`
`Hematology
`
`Forty-third annual
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`
`
`
`
`meeting program
`
`and abstracts
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`
`December 7-11. 2001
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`
`Orlando, Florida
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` *2 .
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`9‘
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`DR. REDDY’S LABS., INC. EX. 1075 PAGE 1
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`

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`PROGRAM OF THE 43RD ANNUAL MEETING OF
`
`THE AMERICAN SOCIETY OF HEMATOLOGY
`
`Decemb er 7-11, 2001
`
`Orlando, Florida
`
`Printed in the USA
`Copyright© 200 1, The American Society of Hematology, Washington, D.C .
`
`DR. REDDY’S LABS., INC. EX. 1075 PAGE 2
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`

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`NOVEL MYELOMA THERAPIES
`
`Ab stract# 3224
`
`Apoptotic S ig n a li ng Induced b y Immunomodulatory Thalidomid e
`Anal o g s ( I m i d s )
`in Human Multiple M y el oma Ce ll s : Therapeuti c
`Implica tion s. Nicholas M itsiades* , 1 Consta n ti ne S. Mitsia des*, ' Vassi liki
`Poulak i *,' Masaharu Akiyama* , ' Yu -Tzu Tai*,' Boris K . Lin* , ' Tosh iaki
`Hayashi",' Lawrence Calley* ,' Teru H id e shim a *,' Dharminde r C hauhan* ,'
`Steven P. Treon" ,' Kenneth C. A n derson. '
`I Department of Adult Oncology.
`Dana Farber Cancer Institute. Boston. MA ; lMassachlisetts Eye and Ear
`Infirmary, Boston, MA.
`Thalidomide (Thai) achieves responses even in the setting ofrefractory multiple myeloma
`(MM). Although increased angiogenesis in MM bo ne marrow and the anti -angiogenic
`effectof ThaI formed the empiric basis for its use in MM, Tha I and its immunomodulatory
`analogs (IMiDs) may also inhibit the production of cytokines in the bon e marrow and
`stimulateNK cell anti -MM immunity. Our prior studies have also demonstra ted that IMiDI
`(Celgene, Warren , NJ) is several-fold mo re potent than Thai in inhibiting the growt h ofMM
`cellsand directly induces apoptosis in the M M. IS MM ce ll line. We therefore invest igate d
`funherthe mechanism of its pro-apoptotic activity, in particular the role of caspases and the
`pro-survival transcription facto r NF-kB. Usi ng a colorimetric activity assay , we found that
`IMiDI induced cas pase-S, but not caspase-9, activity in MM . IS ce lls. Moreover, the caspase(cid:173)
`8 specific inhibitor IETD- FMK , but not the caspase 9 inhibi tor LE HD-F MK, prote cted
`MM.IS cells from IMiDI-induced cell death . Cas pase -8 is a key mediator ofdeath receptor(cid:173)
`mediated apop tosis and can be inhib ited by the anti-apoptotic protein s c1AP2 and FLIP.
`We found that lM iDI sensit ized MM . IS cells to low concentrations of Fas-cros slinking Ab
`CH1\ , and do wnregulated c1AP 2 and FLIP, but not BcI-2, protein expre ssio n. The
`constitutive act ivity of NF-KB, a pro-surv ival transcri ption factor that upregulates c1AP2
`andFLIP expression in various mode ls, was also dec reased upon treatment with IM iD I, as
`wasthe expression of another NF- kB target gene, the adhesio n molecule ICAM- I. IMiD I
`alsoblocked the stimulatory effec t of Insu lin-like Growth Facto r (IGF)- I on NF-KB activity
`and c1AP2 and FLIP protei n levels. Importan tly, (MiD I poten tiated the anti-MM act ivity
`ofdexamethasone and the proteaso me inhibitor PS341 (Mille nniu m, Cambridge, MA). These
`studiesboth delineate the mechanis ms ofactio n of IM iD I aga inst MM ce lls in vitro and form
`the basis for clinical trials of these agents, alo ne and coupled with conve ntional and other
`noveltherap ies, to improve outcome in MM.
`
`Ab stract# 3225
`I
`Immunomodulatory
`an
`S t u dy of Oral CC 5 0 13,
`A Pha s e
`Th alidomide (T h a I)
`D eri vati v e ,
`in Pati ent s with Relapsed and
`Refra ct ory Multiple Myelom a
`( M M),
`P, G. R ich ard s on , ' R . L.
`Schlossm an ,' T, Hideshima,' F. D a v ie s,' R , LeBlanc ,' L. Carley,' 0 , D o ss *,'
`K.A . K e ll y * ,' M . Mc Ke n ney* ,' J . Mec h low icz*,' A . Fre eman * ,' R .
`Deoca m po *,' R . R ic h * ,' 1. R yo o *,' D . C hau han ,' N. Mun shi,' E . Weller*,'
`S. Thomas",' J . Zeldis,' K .C. A n derso n . '
`' Dana-Farber Cancer Institut e,
`Boston. MA. USA; ' Celgene Inc.. Warren. NJ. USA.
`Intr odu ction : Thalidomide (thai) has a broad spectrum ofbiologic effects and signi fican t
`clinical activity against multip le myeloma (M M). CC-50 13,a small molecule derivative of
`thai and a member of the immu nom od ulatory drug (IMiD) clas s, is more potent than thai in
`mediating direct , cytokine-re lated and imm unomo dulatory effec ts agai nst hum an MM ce ll
`linesand patient (pt) derived ce lls in vitro . Anima l studies ofCC-50 13 have shown anti(cid:173)
`MM activity and anti-a ngiogenic effects, wit h minimal toxicity. Moreover, th is age nt has
`a favorable safety profile in norm al hum an voluntee rs. Methods: A phase I study has been
`performed in pts with refractory or relapsed MM to identify the maximum tolerated dose and
`to evaluate the safety of CC- 50 13 given orally for up to 4 weeks at 5 mg/d ay (d), 10 mg/d,
`25 mg/d and 50 mg/d . Seco nda ry objectives inclu ded evaluation of respon se to CC-50 13,
`as well as pharm acok ineti cs and identification of surroga te markers to aid in defi ning
`to
`mechanism s of action. Pts tolerating dru g and with out pro gression were pe rm itted
`continue on therapy beyond 28d as part of an extension phase for up to I year. Results: 26
`pts (median age 57y, range 40-70y) have been enrolled; 16 had undergone prior autologo us
`stemcell
`tra nsplanta tion and 16 had received prior thai, with a median of 3 prior regimens
`(range 2-6). All pts had relapsed MM and 18 were refractory to salvage therap y. 2 pts were
`removed from study on the first day oftreattnent due to rapid disease prog ressio n with renal
`dysfunction that rendered them inel igible . The first gro up of 3 pts were treate d for 28 d at
`5 mg/d without any dose limit ing toxicity (DLT). The second cohort of 3 pts co mmenced
`therapy at 10 mg/d .
`In I pt, DLT was encou ntered wit h gra de (G) 2 fever as we ll as G3
`leukopenia and neutropenia, resulti ng in removal from study befo re d 28 . 2 pts tolerated
`drug and 3 additional pts were treated at 10 mg/d wit h no attributable toxicity within the
`first28d. In the third cohort of3 pts at 25mg/d, drug was well tolerated within the first 28d
`but G3 and G4 thrombocytopenia and neutropenia occ urred during the seco nd month,
`resulting in 2 pts being removed from study. In the fourth cohort at 50mg/d, the first 3 pts
`tolerated treattnent without DLT in the first 28d, but subsequent G3 mye losuppression in
`the extension phase prompted dose red uction and GCSF support. To date, a further 8 pts
`have been treated at 50m g/d to bette r defi ne
`toxicity and o utcome. No DLT has been
`encountered within the first 28d, and no significant som nolence, constipation or neuropathy
`hasbeen seen in any cohort. Median duration oftherapy is cu rrently 2 mont hs [range I wee k
`- 9 months] and 16 pts continue on trea ttne nt. Maximal para protei n reductio ns see n during
`therapy in pts who have received ~ 28d of treatm ent are summarized below :
`< 25% ~2 5 %<5 0% ~ O%
`Dose[mg]
`pis [n]
`progression
`5
`3
`2
`1
`10
`5
`1
`2
`lS
`3
`3
`W
`8
`(4)
`(5)
`(7)
`(3)
`(subtotals)
`( 19)
`Best responses in paraprotei n with a red uction of z 25% have been seen in 12 of 19
`
`4
`
`775a
`
`eval uable pts (63%) and <25% in an additional 3 pts, C oncl us ion: This study shows that
`CC-50 13 has anti-tumo r activity and acc eptable toxicity in pts with relapsed and refractory
`MM, and provi des the framework for futu re phase II trials in MM .
`
`Ab stract# 3226
`
`Result s of Phase I Study of CC-5013 for the Treatment of Multipl e
`M y eloma
`( M M ) Patient s Who
`R elap s e
`after H i gh D o s e
`Chemotherapy ( H D C T). M aurizio Z angari,' G ui d o Tricot ,' Jerome Zeldis,'
`I My elom a and
`P au l E d d le mon*,' Fari b a S aghafi fa r* ,' B a r t B arl o gi e. '
`Transplanta tio n Research Center, University of A rka nsas for Medical
`Scie nces . Little Rock, AR, USA; ' Celgene. Warren. NJ. USA.
`Despite the 40%-50 complete respon se rate and increased surv iva l achieved by high
`dose chemot hera py, there is a clea r need to further improve trea tment outco me in MM . We
`dose, phas e I-study of the
`report results from a sing le center, open label , escalating
`thalidom ide derivative CC -501 3. Four different dai ly dose leve ls (5/ 10/25 /50 mg) we re
`tested. All patient s were treated for four weeks. In the absen ce of dose-lim iting toxicity
`(DLn or evidence of disease progression (PD), patients could be ente red on an ex tension
`study, which allowed furth er dose esca lations. Th e maximum dose allowed in this study
`If at any level one of the first 3 patients ex perie nced DLT, the co hort was
`was 50 mg/d ay.
`ex panded to 6 patient s; if 2 patient s experienced DTL in the sa me co hort, no furthe r dose
`escalation was allowed. Fiftee n patients were enro lled; 6 were ma les . Med ian age was 62
`yea rs (43-7 3); med ian 13-2 micro glob ulin was 2.6 mg/l (1.4-6.4), median CRP 0.24 mg/I (.09
`to 3.7). Ten had chromosome 13 abnorma lities on cyt oge netic anal ysis. All pat ients had
`chem orefra ctory diseas e having relapsed after at least one HDCT (ran ge I to 3) with a
`median of 10 prior cycles of chem otherap y (range 3 to 80). No responses were see n at the
`5 and 10 mg level. However, 2 of the 3 patients, who started at 10 mg and were subse quently
`esca lated on the extension study to 25 and 50 mg, res pec tive ly, achieved a > 50% parap rotein
`response with a decrease in BM plasmacytosis of 50% in one patient, while the other
`co ntinued to show < 5% bone marrow plasm a ce lls. One patient at the 25 mg level had stable
`paraprotein and bone marrow pla smacytosis for 5 month s, while discont inuation of therapy
`was requ ired in 2 patients (one synco pe; one PO ). Six patients started at 50 mg/ day; 3 are '
`sti ll on study, one with stable, one with > 25% and one with> 50 % in both para pro tein level
`and bon e ma rrow plasm acyto sis; 2 patient s ex pe rie nced DLT (thro mboe mbolism an d
`profo und thro mbocytopenia) and one PD. Six patients con tinue on this study after 2, 2, 4,
`5,6 and 6 months, five at 50 mg/d ay and one at 25 mg/day dose. Five of these patients have
`experienced a > 50% drop in platelet cou nt. The initial platelet co unt in these 5 patient s was
`> 140,000/).11 and their bo ne marrow bio psy cellularity > 30%. We co nclu de that 20% of
`these heavily pret reated M M patient s showed a > 50 % paraprotein reduction wi th a
`concomitant bone marrow response . Responses were only observed at the 25 and 50 mg
`dose . Ho w e ve r,
`the
`th al id om ide de r iva tive appears to a lso cause significant
`myelosuppr ession even in pat ients with adequate pla te let co unts and bone marrow
`cellularity before the start of treatm en t. It also has the potential
`to cause cardiovascular
`problems such as throm boe mbol ism and syncope. Neuro logic toxicity is minimal.
`
`A bs t r a c t# 3227
`
`Single Subcutaneous Dose of an O steoprotegerin (OP G )
`A
`a Profound and S us t a i ne d
`Con struct
`(A M GN- 0 0 0 7)
`C a u s e s
`D ecrease of Bone Resorption Comparable to S t a n d a r d
`Intravenou s
`Bispho sphonate in Patients with Multiple M yeloma. P. Greipp. ' T .
`Facon,' C. D . Will ia ms, ' A . L ip to n ,' X . M ariette * ,' J .-P. Ferrn and ," J .
`Ber enson ," J .- L. Harou sseau. ! R . A lexan ian ," A . N akani s hi *, '0 D .
`Holl oway" ;" C. R . Dunstan * , '0 P.1 . B e kker* . 10 I Mayo Clinic, Rochester,
`MN; lCH U de Lille, Lille, France; ' Christie Hosp ital. Manchester, United
`Kingdom; ' Hershey Medical Center, Hershey. PA; ' CH U de Bicetre, Paris,
`France; "Hop ital Sa int-Lo uis, Paris, France; ' Cedars Sinai Med Ctr; Los
`Angeles. CA.' "Hop ital Hotel Dieu, Nantes. France; 9MD Anderson Med Ctr;
`Houston, TX ; /OAmgen Inc. Thousand Oaks, CA.
`Bone destruction causes significant morbidity in most patients with multiple myeloma
`(MM). Cytokines released during bone destruction prom ote myelom a cell proliferation and
`survival. OPG is a potent inhibitor of osteoc lastic bone destruction . A randomize d, double(cid:173)
`blind, do uble-dummy, ac tive-co ntro lled, sing le-dose, dose escalation stu dy is bei ng
`co nducted to determ ine the safe ty and effec t on bo ne resorption of AMGN-0007 in MM
`patients wit h radio log ica l co nfirmed lytic bon e lesion s. Patients were rando mize d (3 : I
`ratio) to receive a sing le dose of either AMGN-0007 SC or pamidronate (PAM ; 90 mg IV)
`and were followe d for 57 days. Medica tions or ot her diseases affecti ng bo ne metabolism
`and chemo therapy within 28 days of dosing were excl usio n criteria. Biological activity of
`AMGN-0007 was assessed by measureme nt of the surrogate ma rker of bo ne resorption,
`urinary N-telopeptide of collagen (NTX). Preliminary data indicate that SC AMGN-0007
`caused a rapi d, sustained dose-depend ent decrease in NTX/creatinine levels (nmol Bone
`Collagen Equivalents/m mol creat inine) . No patients dropped out due to adverse events.
`Two patients in the 1.0 mg/kg AMGN-0007 group had albumin-adjusted serum calcium
`In conclusion, a
`levels of7.4 and 7.5 mg/dL at day 8, but there were no clinical seq uelae.
`sing le SC dose of AMGN-0007 su pp ressed bone resorption as indicated by a rapid,
`sustai ned, and profound decr ease ofurinary NTX/creatinine in MM patie nts. Changes were
`co mparab le to those with PAM. AMGN-0007 was well to lerate d.
`UnDan NIX/Creati nine levels aft er AMGN -Q007 or PAM
`Study Drug
`AMG N-0007
`SC (mglkg)
`0.1 (0=3)
`0.3 (o~)
`1.0 (0- 7)
`3.0 (0=6)
`PAM 90 mg
`I V (0=6)
`
`Per cent Change from Baseline NTX ; Mean (Scj
`Day 1
`Day 8
`Day 29
`-11.7 (20.2)
`-20.5 (20.3)
`-2.8 (6.4)
`-28.6 (5.3)
`-53.7 (11.9)
`-44.8 (9.9)
`-37.9 (14.2)
`-56.\ (7.0)
`-58.8 (6.6)
`-32.5 ( 12.6)
`-46.4 (14.7)
`-34.7 (16.9)
`·36 .9 (5.7)
`-53.9 (8.4)
`-32.4 (9.7)
`
`Baseline NI X; Mean (SDj
`Day 0
`46.3 (33.1)
`27.3 (16.2)
`27.8 ( 11.7)
`27.8 (17.2)
`24.8 ( 11.3)
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`DR. REDDY’S LABS., INC. EX. 1075 PAGE 3
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