November20, 2001
`
`HEALTH SCIENCES
`LIBRARIES
`
`VOLUME 98
`
`Dt) aS ae
`
`NOVEMBER 16, 2001
`
`a nO) ea
`
`American Society of
`
`Hematology
`
`Forty-third annual
`
`Celgene Ex. 2010, Page 1
`
`meeting program
`and abstracts
`
`OT Totti ol] a eo ea
`
`Orlando, Florida
`
`PR2018-01/14
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`IPR2018-01714
`Celgene Ex. 2010, Page 1
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`PROGRAM OFTHE 43RD ANNUAL MEETING OF
`
`THE AMERICAN SOCIETY OF HEMATOLOGY
`
`December 7-11, 2001
`
`Orlando, Florida
`
`Printed in the USA
`Copyright© 2001, The American Society of Hematology, Washington, D.C.
`
`IPR2018-0171
`Celgene Ex. 2010, Page 2
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`IPR2018-01714
`Celgene Ex. 2010, Page 2
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`

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`evaluable pts (63%) and <25% in an additional 3 pts. Conclusion: This study shows that
`CC-5013 has anti-tumoractivity and acceptable toxicity in pts with relapsed and refractory
`MM,and provides the framework for future phase II trials in MM.
`
`Abstract# 3226
`
`775a
`
`MYELOMA THERAPIES
`
`et# 3224
`
`optotic Signaling Induced by Immunomodulatory Thalidomide
`ogs (Imids) in Human Multiple Myeloma Cells: Therapeutic
`ications. Nicholas Mitsiades*,' Constantine S. Mitsiades*,' Vassiliki
`i*,? Masaharu Akiyama*,' Yu-Tzu Tai*,' Boris K. Lin*,' Toshiaki
`yashi*,' Lawrence Catley*,' Teru Hideshima*,' Dharminder Chauhan*,'
`P. Treon*,' Kenneth C. Anderson.' ‘Department of Adult Oncology,
`gna Farber Cancer Institute, Boston, MA; *Massachusetis Eye and Ear
`rmary, Boston, MA.
`“Thalidomide (Thal) achieves responses even in the setting ofrefractory multiple myeloma
`MM). Although increased angiogenesis in MM bone marrow and the anti-angiogenic
`ct ofThal formed the empiric basis for its use in MM,Thaland its immunomodulatory
`gs
`(IMiDs) mayalso inhibit the production of cytokines in the bone marrow and
`ite NK cell anti-MM immunity. Our prior studies have also demonstrated that IMiD1
`Warren, NJ) is several-fold more potent than Thal in inhibiting the growth ofMM
`and directly induces apoptosis in the MM.1S MM cellline. We therefore investigated
`er the mechanism ofits pro-apoptotic activity, in particular the role ofcaspases and the
`urvival transcription factor NF-kB. Using a colorimetric activity assay, we found that
`MiD1 induced caspase-8, but not caspase-9,activity in MM.1S cells. Moreover,the caspase-
`ecific inhibitor IETD-FMK,but not the caspase 9 inhibitor LEHD-FMK,protected
`1S cells from IMiD1-induced cell death, Caspase-8 is a key mediator ofdeath receptor-
`ted apoptosis and can be inhibited by the anti-apoptotic proteins cLAP2 and FLIP.
`found that IMiD1 sensitized MM.1S cells to low concentrations of Fas-crosslinking Ab
`Hi, and downregulated clAP2 and FLIP, but not Bel-2, protein expression. The
`itutive activity of NF-KB, a pro-survival transcription factor that upregulates clAP2
`FLIP expression in various models, was also decreased upon treatment with IMiD1, as
`the expression of another NF-kB target gene, the adhesion molecule ICAM-1. IMiD1
`9 blocked the stimulatory effect of Insulin-like Growth Factor (IGF)-1 on NF-KBactivity
`prar2 and FLIP protein levels. Importantly, IMiD1 potentiated the anti-MMactivity
`e)
`asone
`and the proteasome inhibitor PS341 (Millennium, Cambridge, MA). These
`dies both delineate the mechanisms ofaction of IMiD1 against MMcellsin vitro and form
`basis for clinical trials of these agents, alone and coupled with conventional and other
`ovel therapies, to improve outcome in MM.
`
`problems such as thromboembolism and syncope. Neurologic toxicity is minimal.
`
`Results of Phase I Study of CC-5013 for the Treatment of Multiple
`Myeloma
`(MM) Patients Who Relapse after High Dose
`Chemotherapy (HDCT). Maurizio Zangari,' Guido Tricot,' Jerome Zeldis,’
`Paul Eddlemon*,' Fariba Saghafifar*,' Bart Barlogie.' ‘Myeloma and
`Transplantation Research Center, University of Arkansas for Medical
`Sciences, Little Rock, AR, USA; *Celgene, Warren, NJ, USA.
`Despite the 40%-50 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 I-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 further dose escalations. The maximum dose allowedin this study
`was 50 mg/day. If at any level one ofthe 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 patients were enrolled; 6 were males. Median age was 62
`years (43-73); median -2 microglobulin was 2.6 mg/l (1.4-6.4), median CRP 0.24 mg/l (.09
`to 3.7). Ten had chromosome 13 abnormalities on cytogenetic analysis. All patients had
`chemorefractory disease having relapsed after at least one HDCT (range | to 3) with a
`median of 10 prior cycles of chemotherapy (range 3 to 80). No responses were seen at the
`Sand 10 mg level. However,2 of the 3 patients, whostarted at 10 mg and were subsequently
`escalated on the extension study to 25 and 50 mg,respectively, achieved a > 50%paraprotein
`response with a decrease in BM plasmacytosis of 50%in one patient, while the other
`continued to show < 5% bone marrow plasma cells. One patient at the 25 mg level had stable
`paraprotein and bone marrow plasmacytosis for 5 months, while discontinuation of therapy
`was required in 2 patients (one syncope; one PD), Six patients started at 50 mg/day; 3 are’
`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 after 2, 2, 4,
`5, 6 and 6 months, five at 50 mg/day and one at 25 mg/day dose. Five ofthese patients have
`experienced a > 50% drop in platelet count. The initial platelet count in these 5 patients was
`> 140,000/11 and their bone marrow biopsy cellularity > 30%. We conclude that 20% of
`these heavily pretreated MM_ patients showed a > 50% paraprotein reduction with a
`concomitant bone marrow response. 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
`cellularity before the start of treatment. It also has the potential to cause cardiovascular
`
`Abstract# 3227
`
`Abstract# 3225
`Phase 1 Study of Oral CC5013, an Immunomodulatory
`thalidomide (Thal) Derivative, in Patients with Relapsed and
`efractory Multiple Myeloma
`(MM). P.G. Richardson,' R.L.
`hlossman,' T. Hideshima,' F. Davies,' R. LeBlanc,' L. Catley,' D. Doss*,'
`K.A. Kelly*,' M. McKenney*,' J. Mechlowicz*,' A. Freeman*,' R.
`Deocampo*,' R. Rich*,' J. Ryoo*,' D. Chauhan,' N. Munshi,' E. Weller*,'
`S$. Thomas*,? J. Zeldis,? K.C. Anderson.' ‘Dana-Farber Cancer Institute,
`oston, MA, USA; *Celgene Inc., Warren, NJ, USA.
`_
`Introduction: Thalidomide (thal) has a broad spectrum ofbiologic effects and significant
`linical activity against multiple myeloma (MM). CC-5013, a small molecule derivative of
`Single Subcutaneous Dose of an Osteoprotegerin (OPG)
`A
`and a memberof the immunomodulatory drug (IMiD)class, is more potentthan thal in
`Construct
`(AMGN-0007)
`Causes a Profound and Sustained
`mediating direct, cytokine-related and immunomodulatory effects against haoman MM cell
`Decrease of Bone Resorption Comparable to Standard Intravenous
`es and patient (pt) derived cells in vitro. Animal studies of CC-5013 have shown anti-
`Bisphosphonate in Patients with Multiple Myeloma. P. Greipp,' T.
`activity and anti-angiogenic effects, with minimal toxicity. Moreover, this agent has
`Facon,’? C.D. Williams,’ A. Lipton,* X. Mariette*,’ J.-P. Fermand,® J.
`favorable safety profile in normal human volunteers. Methods: A phase I study has been
`Berenson,’ J.-L. Harousseau,* R. Alexanian,? A. Nakanishi*,'® D.
`erformed in pts with refractory or relapsed MM to identify the maximum tolerated dose and
`Holloway*,'® C.R. Dunstan*,' P.J. Bekker*.'° ‘Mayo Clinic, Rochester,
`evaluate the safety ofCC-5013 given orally for up to 4 weeks at 5 mg/day(d), 10 mg/d,
`25 mg/d and 50 mg/d. Secondary objectives included evaluation of response to CC-5013,
`MN; ?CHUdeLille, Lille, France; *Christie Hospital, Manchester, United
`as well as pharmacokinetics and identification of surrogate markers to aid in defining
`Kingdom; *Hershey Medical Center, Hershey, PA; *CHU de Bicetre, Paris,
`mechanisms of action. Pts tolerating drug and without progression were permitted to
`France; °Hopital Saint-Louis, Paris, France; "Cedars Sinai Med Ctr, Los
`ontinue
`on therapy beyond 28das part ofan extension phase for up to | year. Results: 26
`Angeles, CA; ‘Hopital Hotel Dieu, Nantes, France; "MD Anderson Med Ctr,
`(median age 57y, range 40-70y) have been enrolled; 16 had undergone prior autologous
`Houston, TX;
`'“Amgen Inc, Thousand Oaks, CA.
`stem cell transplantation and 16 had received priorthal, with a median of3 prior regimens
`Bonedestruction causes significant morbidity in most patients with multiple myeloma
`range
`2-6). All pts had relapsed MMand 18 were refractory to salvage therapy. 2 pts were
`(MM). Cytokines released during bone destruction promote myclomacell proliferation and
`oved from study on the first day oftreatment duc to rapid disease progression with renal
`survival. OPG is a potentinhibitor ofosteoclastic bone destruction. A randomized, double-
`dysfunction
`that rendered them ineligible. The first group of 3 pts were treated for 28 d at
`blind, double-dummy, active-controlled, single-dose, dose escalation study is being
`ng/d without any dose limiting toxicity (DLT). The second cohort of 3 pts commenced
`conducted to determine the safety and effect on bone resorption of AMGN-0007 in MM
`ipy
`at 10 mg/d.
`In | pt, DLT was encountered with grade (G) 2 fever as well as G3
`patients with radiological confirmed lytic bone lesions. Patients were randomized (3:1
`copenia and neutropenia, resulting in removal from study before d 28. 2 pts tolerated
`ratio) to receive a single dose of either AMGN-0007 SC or pamidronate (PAM; 90 mg I'V)
`and 3 additional pts were treated at 10 mg/d with no attributable toxicity within the
`and were followed for 57 days. Medications or other diseases affecting bone metabolism
`pst 28d. In the third cohort of 3 pts at 25mg/d, drug was well tolerated within the first 28d
`and chemotherapy within 28 days of dosing were exclusion criteria. Biological activity of
`G3 and G4 thrombocytopenia and neutropenia occurred during the second month,
`AMGN-0007 was assessed by measurementof the surrogate marker of bone resorption,
`urinary N-telopeptide ofcite (NTX). Preliminary data indicate that SC AMGN-0007
`ulting in 2 pts being removed from study. In the fourth cohort at 50mg/d, the first 3. pts
`ted treatment without DLTin the first 28d, but subsequent G3 myelosuppression in
`caused a rapid, sustained dose-dependent decrease in NTX/creatinine levels (nmol Bone
`extension phase prompted dose reduction and GCSF support. To date, a further 8 pts
`Collagen Equivalents/mmol creatinine). No patients dropped out due to adverse events.
`ve been treated at 50mg/d to better define toxicity and outcome. No DLT has been
`Twopatients in the 1.0 mg/kg AMGN-0007 group had albumin-adjusted serum calcium
`ountered 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 | week
`single SC dose of AMGN-0007 suppressed bone resorption as indicated by a rapid,
`7months] and 16 pts continue on treatment. Maximalparaprotein reductions seen during
`sustained, and profound decrease of urinary NTX/creatinine in MM patients. Changes were
`erapy
`in pts who have received 2 28d of treatment are summarized below:
`comparable to those with PAM. AMGN-0007 was well tolerated.
`e{mg)
`pts [n]
`< 25% 225%<50%
`250% progression
`
`
`
`UrinaryNTX/CreatininelevelsafterAMGN-0007orPAM
`3
`-
`2
`1
`-
`Study Drug
`5
`-
`-
`1
`4
`AMGN-0007
`3
`1
`2
`-
`-
`SC (mg/kg)
`8g
`2
`3
`3
`-
`50
`0.1 (n=3)
`(19)
`(3)
`a
`(5)
`(4)
`(subtotals)
`0.3 (n=4)
`Best responses in paraprotein with a reduction of 2 25% have been seen in 12 of 19
`1.0 (n=7)
`3.0 (n=6)
`PAM 90 mg
`IV(n=6)
`
`Baseline NTX; Mean (SD)
`Day 0
`46.3 (33.1)
`27.3 (16.2)
`27.8 (11.7)
`27.8 (17.2)
`24.8 (11.3)
`
`Percent Change from Baseline NT'X; Mean (SE)
`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)
`~56.1 (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)
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