November 20, 2001
`
`HEALTH SCIENCES
`LIBRARIES
`
`
`
`December 7-11. 2001
`
`Orlando. Florida
`
`'R20 3-.
`
`A
`
`Celgene Ex. 2010, Page 1
`
`VOLUME 98
`
`NUMBER 11
`
`NOVEMBER 16, 2001
`
`PART 1 OF 2 PARTS
`
`Amnrrcan Society of
`
`Hematology
`
`Forty-thud annual
`
`meeting program
`and abstracts
`
`IPR2018-01714
`Celgene Ex. 2010, Page 1
`
`

`

`
`
`PROGRAM OF THE 43RD ANNUAL MEETING OF
`
`THE AMERICAN SOCIETY OF HEMATOLOGY
`
`December 7-11, 2001
`
`Orlando, Florida
`
`Copyright© 200 l , The American Society of Hematology, Washington, DC.
`
`Printed in the USA
`
`|PR2018—0171
`
`Celgene Ex. 2010, Page 2
`
`IPR2018-01714
`Celgene Ex. 2010, Page 2
`
`

`

`MYELOMA THERAPIES
`
`CM 3224
`
`_.
`
`\
`
`-
`
`‘
`
`ptotlc Signaling induced by Immunomodulatory Thalidomide
`oga (lmlds) in Human Multiple Myeloma Cells: Therapeutic
`- ~ tions. Nicholas Mitsiades‘,‘ Constantine S. Mitsiades‘,‘ Vassililti
`i‘f Masaharu Akiyama’,‘ Yu-Tzu Tai’,‘ Boris K. Lin‘,‘ Toshiaki
`It‘l Lawrence Catlcy‘,‘ Tel.“ Hideshima‘.‘ Dmmdfl Chauhan‘,‘
`P. Treon',‘ Kenneth C. Anderson.‘ ’Department of Adult Oncology.
`r Farber Cancer Institute. Boston. MA; "Massachusetts Eve and Ear
`nnarv. 305,0". MA.
`'
`IIi'Inlidomide (Thai) achieves recpomeveninthesettingofrefiactory mulfip'emyelm
`I
`. Although increased mgiogenesis in MM bone mmw and [he anti—angio‘enic
`, ofTim] formed the empiric basis for its use in MM. Thai and its immunomodulatory
`7.
`(lMiDa) may also inhibit the production of cytokincs in the bone marrow and
`. NK mu anti-MM immunity. Oufpriof studs“ hm; a)” mnsmred a... lMiDl
`. wm, NJ) is mermaid m pom. aw. Thal in inhibiting the growth ofMM
`and directly induces apoptogis in the MMJS MM cell line, we uremia," investigated
`. the mm)“ or its pro-apoptotic activity, in mm“! the role (ll-W and the
`w
`'val transcription factor NF-kB. Using a colorimetric activity assay, we found that
`‘ "I | WWW-8' but notcaspase-9. activity in MM. lScella. Moreover. the caspase-
`- ific inhibitor lETD-FMK. but not the caspase 9 inhibitor LEHD—FMK. protected
`IS cells fiom lMiDI-indueed cell death. Cum-8 is a key mediator ofdeath receptor.
`apoptosis and can be inhibited by the anti-opoptotic proteins clAPZ and FLIP.
`found that lMiDI sensitized MM.|S cells to low concentrations of Fas-crosslinking Ab
`. 11. and downregulated elAP2 and FLIP, but not Bel-2. protein expression. The
`.'
`'ve activity of NF Kg a PM survival WM" factor that wwsulufl elAP2
`FLIP expression in various models. was also decreased upon treatment with [MD], as
`the expression of another NF-ltB larger gene, the adhesion molecule [CAM-l. lMiDl
`blocked the stimulatory effect orlrsulin-like Growth Factor(lGF)—l on NF-KB activity
`clAl’2 and FLIP protein levels. lmportantly. lMiDl potentiated the anti-MM activity
`2
`.
`. r
`and lheproteesome inhibitor P5341 (Millenniurn.Cambridge, MA). These
`- both delineate the mechanisms ofacllonoflMlDl against MM cellsIn vitroand form
`basis for clinical trials of these agents alone and coupled with conventional and other
`— thean to improve outcome in MM.
`
`,
`
`.
`
`I
`
`‘
`
`.
`
`i
`
`I
`
`‘
`
`in an additional 3 pta. Conclusion: This study shows that
`evaluable pts (63%) and <25"/.
`CC~5013 has anti-tumor activity and acceptable toxicity in pts with relapsed and refractory
`MM. and provides the framework forfilture phase II mm m MM.
`
`775a
`
`
`
`“mm“ 3226
`Results of Pill" I Study of CC-5013 for the Treatment of Multiple
`Myeloma
`(MM) Patients WI” 39"?” “t? High 09‘?
`Chemotherapy (HDCT) Maunzlo 281183", Guido Tneot, Jerome Zeldlsr'
`Paul Eddiemon’,‘ Fanba Sagbafifar‘,‘ Bart Barlogle.l ’Myeloma and
`Transplantation Research Center. University of Arkansas for Medical
`Sciences. Little Rock. AR, USA; ’Celgene, Warren, NJ. USA.
`Dewitt lhc “TI/v50 complete response rate and increased survival achieved by high
`dose chemotherapy, there is a clear need to further improve treatment outcome in MM. We
`report results from a single center, open label. escalating dose. phase l-study of the
`thalidomide derivative CC-5013. Four different daily dose levels (5/ 10/25/50 mg) were
`tested. All patients were treated for four weeks. In the absence of dose-limiting toxicity
`(DLT) or evidence of disease progression (PD), patients could be entered on an extension
`study. which allowed filrther dose escalations. The maximum dose allowed in this study
`was 50 mg/day. if at any level one of the first 3 patients experienced DLT. the cohort was
`expanded to 6 patients; if 2 patients experienced DTL in the same cohort. no further dose
`escalation was allowed. Fifteen pmients were enrolled; 6 were males. Median age was 62
`years (43-73); median In micmslobulin was 2-6 mil/I (1.4-6.4). medim CRP 0.24 mg/I (.09
`to 3.7). Ten had chromosome 13 abnormalities on cytogenetic analysis. All patients had
`chemorefractory disease having ”law after 8‘ least one HDCT (range l ‘0 3) With 3
`median of 10 prior cycles of chemotherapy (range 3 to 80). No responses were seen at the
`S and 10 mg level. However, 2 of the 3 patients, who started at 10 mg and were subsequently
`escalatedon the extension study to 25 and 50 mg, respectively, achieved a> 50% paraprotein
`response with a decrease in BM plasmacywsis of 50% in one patient. while the Other
`continued to show < 5% bone marrow plasma cells. Oncpatienlatthe 25 mg level had stable
`pmprotein and bone marrow plasrnacytosis for 5 months, while discontinuation of therapy
`W Wind in 2 [1311'an (one syncope; 00C PD) 51" patients started 3‘ 5° Ins/day: 3 IN
`still on study. one with stable, one with > 25% and one with> 50 % in both paraprotein level
`and bone marrow plasmacytosis; 2 patients experienced DLT (thromboembolism and
`profound thrombocytopenia) and one PD. Six patients continue on this study alter 2, 2. 4.
`5. 6 and 6 months, five at 50 myday and one at 25 mg/day dose. Five ofthere patients have
`experienced a > 50% drop in platelet count. The initial platelet count in these 5 patients was
`> 140,000/pl and their bone marrow biopsy eellularity > 30%. We conclude that 20% of
`these heavily pretreated MM patients showed a > 50% paraprotein reduction with a
`concomitant bone marrow reapome. Responses were only observed at the 25 and 50 mg
`dose. However. the
`thalidomide derivative appears to also cause significant
`myelosuppression even in patients with adequate platelet counts and bone marrow
`llularity before the start of treatment. it also has the potential to cause cardiovascular
`°°
`I
`.
`.
`.
`.
`.
`.
`.
`pmblems such as mm boll“ "Id synmpe‘ Neuromgw “mew Is "mum"
`Abstractil 3227
`
`\ new 3225
`.
`tn lmmunomodulflory
`» "I" 1 Study of 0"“ CC5013.
`( alidornide (Thai) Derivative, in Patients with Relapaed and
`.. raetory Multiple Myelorna
`(MM). P.G. Riehardson.‘ R.L.
`., 2
`;
`' T. Hideshima,‘ F. Davies.' R. LeBlanc.' L. Catley,‘ D. Dosis‘,I
`' A. Kellytll M. McKenney".I J. Mechlowicz‘.‘ A. Freeman’,‘ R.
`-
`-
`..
`. po‘,‘ R. RICh‘,‘ .l. Ryoo‘,‘ D. Chauhan,‘ N. Munshr,I E. Weller‘,‘
`Thomas‘.2 .1. Zeldis.2 K.C. Anderson.‘ ’Dana-Farber Cancer Institute.
`I ran. MA. USA: ‘Celgene Inc., Warren, NJ. USA.
`;
`Introduction: Thalidomide (tlnl)has a broad spectrum ofbiologic effects andsigrlifieant
`activity against multiple myelomn (MM). CC-5013,asmall molecule derivative of
`Single Subcutaneous Dose of an Osteo rote erin (0P6)
`A
`arlda rrrembcroflhcrrnrrlunomodrrlatory drugthrD)class. rs moreporenl than thal m
`Construct
`(AMCN-0007) Cause: a Profound and Sustained
`' KdIFCI-cfiORIIlC-mlaled mdlmmnf’dulalofxcmfls 3831“!“ human MM 061'
`Decrease of Bone Resorption Comparable to Standard Intravenous
`— andpatlent(pt)dcnved cells in vilra
`. Animal studles ofCC-5013 have shown anu-
`Biaphoaphonate in Patients with Multiple Myeloma. p. Greipp I T.
`activity and anti-angiogenic effects. with minimal toxicity. Moreover. this agent has
`2
`-
`-
`y
`-
`a
`~
`. 5
`_
`I r,
`amblrrarery profile in normal human volunteers. Methods: Aphaseistudyhasbeen
`Saw“: C'Pj X'IIISII‘S' A' “in? A1" Ma."°‘§°A’ is: F‘?";‘.i“fi; 1;"
`-
`-
`-~ ln ptswrthrefractoryorrelapsed MM tordentlfy themarumumtolerateddoseand
`erenson; lo '
`'
`arousseag.
`‘
`exaitllgnl.
`‘
`d ants I
`‘
`'
`mm the “My ofCC-5013 given on“), for up w 4 weeks a. 5 "IE/day (d). 10 mg/d,
`Holloway . C.R. Dunstan , PJ. Bekker . Mayo Cllnlc, Rochester;
`, nlg/d and 50 mg/d. swung"). objectives included ewiuflfion of response .0 c050”,
`.
`MN: ‘ICHU de Lille. Lille. France; ’Christie Hospital. Manchester. United
`_ well as phannncokinetics and identification of surrogate markers to aid in defining
`Kingdom; ‘Hershey Medical Center, Hershey. PA; ’CHU de Bicetre. Paris.
`. ..
`. isms of action. Pts tolerating dmg and without progression were permitted to
`France: “Hopital Saint-Louis. Paris. France; 7Cedars Sinai Med Ctr. Los
`-
`2 H
`.0" my beyond 28“ aspanofan extension PM for “D10 | year. “all“: 26
`Angeles, CA; 'Hopl'tal Hotel Dl'eu. Nantes. France: "MD Anderson Med Ctr:
`(lrledlarl age 57y, range 40-70y) have been enrolled; 16 had undergone prior autologous
`Houston, TX;
`inAmgen Inc, Thousand Oaks. CA.
`In cell transplantationand lohadreoeivedpriorthal.withamedianof3priortegimens
`2-6). All us had "I
`MM and 18 were refractory to salvage th
`. 2 m were
`Bone desmrctlon causes srguficant morbidity In most patients Wlth multiple myeloma
`'
`(MM). Cytokinea released during bone destruction romote m lonta cell proliferation and
`‘ °"mfiymm 9yl9fzfigmfl° ‘° “P"3”“ W532"? “m"
`survival. ore is a potent inhibitorofosteoclnstic btfne demucfizn. A modernized, double-
`I
`'
`ren
`II" '8'
`e
`e
`rst ”WP"
`ptswere MI
`or 8 d 'I
`blind, double-dummy. active-controlled, single-dose. dose escalation study is being
`d WIIII‘IIII any 6°“ III'IIIIIIIB ”IIICI‘Y (DLT). The second cohort “f3 P“ commenced
`conducted to determine the safety and effect on bone resorption of AMGN-0007 in MM
`'
`8.! I0 ngd In I PI‘ DLT w.mm°"d WIIII M (G) 2 fever as “II as 03
`patients with radiological confirmed lytic bone lesions. Patients were randomized (3:1
`" '
`a “lW“ “mm“! "‘ ””0"" “2"“ “My ”9“" " 28- ,2?“ ‘_°"i“‘°“
`ratio) to receive a single dose ofeither AMGN-DOO’T sc or pamidronate (PAM; 90 mg 1V)
`'“d 3 ““9“ P“ “m m“ 2“ '0 "‘8" “m" "0 “mm“ ‘°.’“F"Y “"“l'” “‘e
`and were followed for 57 days. Medications or other diseases affecting bone metabolism
`’ 2“- '" “‘° “W °°h°" ”13 P" “ 25mg" “”3 "'3 W" ”W “"‘h'n "'e “‘3‘ 23d
`and chemotherapy within 28 days of dosing were exclusion criteria. Biological activity of
`.6'3 "'d 204 wwfl "gym: “cw during III: mumw
`AMGN-0007 was assessed by mmment of the surrogate marker of bone resorption.
`-
`4. "I P”
`"38 m ,m Y~ "
`“In“ W a! 50m!“-
`. P,"
`urinary N-telopeptidc of collagen (NTX). Preliminary data indicate that sc AMGN—0007
`"'
`.III
`I III Without DLT III III: III? 28d’ but subsequent G3 myelosuppteaston III
`caused a rapid, sllstained dose-dependent decrease in NTX/creatinine levels (nmoi Bone
`extension PM” prompted do“ reduction ”d GCSF W' T° date, a M“ 8 pts
`Collagen Equivalents/ml creatinine). No patients dropped out due to adverse events.
`. been treated at SOmyd to better define toxrctty and outcome. No DLT bu been
`Two patients in the 1.0 mg/ltg AMGN-0007 81'9“? had albuninodjwted serum calcium
`-
`. tered within the first 28d, and no significant somnolence. constipation or neuropathy
`levels of 7.4 and 7.5 mg/dL at day 8. but there were no clinical sequelae.
`In conclusion, a
`been seen in any cohort. Median duration oftherapy is currently 2 months [range 1 week
`single SC dose of AMGN-0007 suppressed bone resorption as indicated by a rapid.
`_ months] and 16 pts continue on treatment. Maximal paraprotein reductions seen during
`sustained. and profound decrease of urinary NTX/creatinine in MM patients. Changes were
`..
`in pts who have received 2 28d of treatment are summarized below:
`~
`“'2’ 2““
`‘2’“
`2.5.2.5...
`2"“ W2" mow"MW ”W'mk'“
`9",,
`3
`.
`2
`l
`.
`SM,
`i
`i
`i
`I
`f
`AMGN-ooln
`a
`2
`3
`3
`.
`SC (ms/kw
`2:2
`m 12:7:
`3.0 “PM
`PAM 90 II:
`[V (n-ol
`
`‘
`I
`
`‘
`
`,
`
`.
`'-
`E.
`-
`
`2
`
`Best responses in Paraprotein with a
`
`lion of 2 25% have
`
`.
`
`seen in 12 of 19
`
`linen-re NTX; Mean no)
`Dry 0
`222222
`2728 :l '17;
`27.8 (I71)
`2428 (NJ)
`
`Percent Change nan Baseline N'rx; Mean (SE)
`Day 1
`Day a
`Day 29
`2.22::
`68:8 16:6:
`.347 (16.9)
`.324 (9.7)
`
`:56:‘ lilti)’
`46.4 (14.7)
`43.9 (3.4)
`
`57:9 Elli)
`.325 (12.6)
`66.9 (5.7)
`
`lPR2018—O1714
`
`Celgene Ex. 2010, Page 3
`
`IPR2018-01714
`Celgene Ex. 2010, Page 3
`
`