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`ABSTRACTS
`
`CHEMOTHERAPY FOUNDATION SYMPOSIUIVI XXI
`
`INNOVATIVE CANCER THERAPY FOR TOMORROW
`
`Presented on
`November 12-15, 2003
`New York, NY, USA
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`EBLING LIBRARY
`UNIVERSITYITYOF WISCONSIN
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`JUN 23 2004
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`750 Highland Avenue
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`This Supplement ls Sponsored by an Unrestricted Educational Grant from
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`Genentech
`BIOQNCOLOGY
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`M A R C E L
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`The Official Journal of The Chemotherapy Foundation and The Inter-American Society for Chemotherapy (IASC)
`
`n Volume 22
`
`o s KXER
`
`Supplement 1
`
`2004
`
`IPR2018—01509
`Exhibit 2028, Page 1
`
`
`
`

`

`CANCER INVESTIGATION
`
`Aims and Scope. Cancer Investigation is designed to provide workers in both the basic and clinical sciences who need
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`Dr. Reddy’s Laboratories, Inc. v. Celgene Coup.
`IPR2018—01509
`Exhibit 2028, Page 2
`
`

`

`CANCER INVESTIGATION
`
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`Dr. Reddy’s Laboratories, Inc. v. Oelgene Corp.
`IPR2018—01509
`Exhibit 2028, Page 3
`
`

`

`Abstracts
`
`15
`
`10. Tirnmerman, J.M.; Czerwinski, D.; Taidi, B., et al.
`A phase III] trial to evaluate the immunogenicity
`of recombinant idiotype protein vaccines for the
`treatment of non-Hodgkin’s lymphoma (NI-IL).
`Blood 2000, 96, 578a.
`11. Osterroth, F.; Garbe, A.; Fisch, P.; Veelken, H.
`
`Stimulation of cytotoxic T cells against idiotype
`immunoglobulin of malignant
`lymphoma with
`protein-pulsed or
`idiotype-transduced dendritic
`cells. Blood 2000, 95, 1342—1349.
`12. McCormick, A.A.; Kumagai, M.H.; Hanley, K.,
`et a1. Rapid production of specific vaccines for
`lymphoma by expression of the tumor-derived
`single—chain Fv epitopes in tobacco plants. Proc.
`Natl. Acad. Sci. U.S.A. 1999, 96, 703—708.
`13. King, C.A.; Spellerberg, M.B.; Zhu, D., et a1. DNA
`vaccines with single-chain Fv fused to fragment C
`of tetanus toxin induce protective immunity
`against
`lymphoma and myeloma. Nat. Med.
`1998, 4, 1281—1286.
`
`9. ERYTHROPOIETIC REMITTING
`ACTIVITY OF THE IMMUNOMODULATORY
`THALIDOMIDE ANALOG CCS013
`
`(REVIMIDn‘) IN PATIENTS WITH
`MYELODYSPLASTIC SYNDROME
`
`(MDS): RESULTS OF A PHASE I/II TRIAL
`
`Alan List, Sandy Kurtin, Betty Gibson, William Bel—
`lamy, Dorothy Waddelton, and Robert Knight The
`Arizona Cancer Center and the University of Arizona
`College of Medicine, Tucson, Arizona 85724; and
`Celgene Inc, Warren. New Jersey 07059
`
`Thalidomide improves erythropoiesis in approxi-
`mately 20% of patients with MDS, but is limited by cu-
`mulative neurological toxicity.“’2] CC5013 (Revimidm)
`is an immunomodulatory (IMiD) derivative which dis—
`plays lOO—fold greater suppression of TNFa generation,
`and lacks the neurologic effects of the parent com—
`pound.[3'4] The pharmacologic effects of CC5013 derive
`from its multiple relevant biological targets including its
`action as an inhibitor of cellular response to receptor-
`initiated trophic signals (e.g., insulin-like growth fac-
`tor-I, vascular endothelial growth factor [VEGF], cy—
`clooxygenase-2), and blockade of constitutive NF-KB
`transactivationpl As a result, CC5013 suppresses the
`generation of inflammatory cytokines, alters cell adhe-
`sion while suppressing apoptosis inhibitory proteins
`
`(e.g., cFLIP, cIAP) and promoting sensitivity to death-
`receptor initiated programmed cell death. We have
`shown that CC5013 abrogates mitogenic response to
`VEGF in AML cells by inhibiting ligand—induced acti-
`vation of phosphotidylinositol—3’ kinase/Akt signaling
`and down«regulating VEGF gene transcription, and se-
`lectively promotes adhesion of MDS mononuclear and
`CD34+ cells to bone marrow stroma while enhancing
`susceptibility to fas ligand induced cell deathm These
`findings indicate that CC5013 selectively suppresses
`proliferation of MDS clones by inhibiting VEGF—in-
`duced autocrine signals, corresponding angiogenic re-
`sponse and restoring stromal cell adhesion.
`To evaluate the remitting potential of CC5013 in
`MDS, we performed a Phase [III trial in patients with
`red blood cell (RBC) transfusion—dependent (i.e., >4
`units/8 wks) or
`symptomatic anemia
`(hemoglobin
`[Hgb]<9 g/dl) with neutropenia or thrombocytopenia
`less than NCI-Comrnon Toxicity Criteria (CTC) defined
`grade 4. Patients received treatment with either 25 mg
`or 10 mg CC5013 in a continuous oral daily dosing
`schedule, or 10 mg/day x21 days following by 1 week
`treatment hiatus (i.e.,
`‘Syncopated Schedule’). Drug
`tolerance was assessed at 4 week intervals and response
`was assessed according to the International Working
`Group (IWG) criteria after 16 weeks of study treatment.
`Forty-two patients have been registered for
`study
`treatment, and 25 are evaluable for response after
`completing 8 weeks or more of study treatment. Among
`non—evaluable patients, 10 are too early (i.e.,<8 weeks);
`5 discontinued treatment prematurely (<4 weeks) due to
`unrecognized autoimmune hemolytic anemia,
`[1] con—
`sent withdrawal [2] or myelosuppression [2]; and suc-
`cumbed to two infectious complications unrelated to
`study treatment. Median age is 74 years [range: 51—85].
`FAB types include RA [12], RARS [7], RAEB [5], and
`RAEB-t [l] with corresponding IPSS categories of
`Low/Intermediate (Int)—l, 21 patients;
`Int—2/High, 4
`patients. Eight patients (32%) failed prior treatment
`with thalidomide. Myelosuppression, characterized by
`>grade 3 NCl—CTC or 50% decrease in leukocyte and
`platelet counts [9 pts], or grade 3 fatigue [n=1] neces-
`sitated dose reduction in each of the ten subjects re-
`ceiving the 25 mg dose, compared to 9 of 13 patients
`receiving the continuous 10mg schedule. Interval
`to
`limiting myelosuppression was dose dependent, median
`number of weeks at 25 mg/d, 4+2 (range, 3—8); versus
`10 mg/d, 13+6 weeks (range 2—20). Grade 1 or 2 ad-
`verse effects were uncommon and limited to transient
`
`scalp pruritus [8 patients] or urticaria [2 patients], di-
`arrhea [6 patients], joint pain [4 patients], hypothyroid
`[1 patient], and" fatigue [2 patients]. Sixteen (64%) of
`
`Dr. Reddy’s Laboratories, Inc. v. Celgene Corp.
`IPR201 8-01 509
`Exlibit 2028, Page 4
`
`

`

`16
`
`Abstracts
`
`25 evaluable patients experienced an IWG—defined
`erythroid response,
`including major
`responses
`(i.e..
`transfusion-independence or >2 g Hgb increase) in 12
`patients, and >50% decrease in RBC transfusions in 4
`patients. Response rate was greater in patients with RA
`or RARS (14/19, 75%), Low/Int—l IPSS risk score (15/
`21. 71 %), and 5q31—33 interstitial chromosome deletion
`(8/8). Among 13 patients with an abnormal karyotype, 9
`(69%) experienced a major cytogenetic response.
`in-
`cluding restoration of a normal karyotype in 8 patients.
`Responses were associated with normalization of blast
`percentage in 2/6 patients (33%), reduced grade of bone
`marrow (BM) cytologic dysplasia, and 50% to >40’-fold
`improvement in BM CFU-GEMM and BFU-E forma—
`tion. Bone marrow (BM) apoptotic index increased 2.5
`to 5-fold and microvessel density (MVD) and BM
`plasma VEGF decreased in responding patients, whereas
`MVD increased in non—responders. The preliminary
`results of this study indicate that CC5013 has remark-
`able erythropoietic and cytogenetic remitting activity in
`patients with bow/Int-l n’sk MDS. The increase in ap-
`optotic index, restoration of colony-forming capacity,
`and suppression of clonal karyotypic abnormalities
`suggest that CC5013 promotes extinction of sensitive
`myelodysplastic clones. Myelosuppression is common
`and directly related to dose and cumulative drug expo-
`sure. Two multicenter phase II studies are underway to
`define the erythroid response rate in patients with the
`5q-syndrome or non—5q— Low/Int—l MDS.
`
`REFERENCES
`
`l. Raza, A.; Meyer, P.; Dutt, D., et a1. Thalidomide
`produces transfusion independence in long-stand-
`ing refractory anemias of patients with myelodys-
`plastic syndromes. Blood 2001, 98, 958—965.
`2. Zorat, F.; Shetty, V.; Dutt, D., et al. The clinical
`and biological effects of thalidomide in patients
`with myelodysplastic syndrome. Br. J. Haematol.
`2001, 115, 881—894.
`3. Corral, L.G.; Haslett, P.A.; Muller, G.W., et a].
`Differential cytokine modulation and T cell
`activation by two distinct classes of thalidomide
`analogues that are potent inhibitors of TNF alpha.
`J. Immunol. 1999, 163, 380-386.
`a1.
`4. Davies. F.E.; Raje. N.; Hideshima, T., et
`Thalidomide and immunomodulatory derivatives
`augment natural killer cell cytotoxicity in multiple
`myeloma. Blood 2001, 98, 210—216.
`5. List, A.F.; Tate, W.; Glinsmann-Gibson, B.J., et al.
`The immunomodulatory thalidomide analog,
`CC5013,
`inhibits trophic response to VEGF in
`
`AML cells by abolishing cytokine-induced P13—
`kinase/Akt activation. Blood 2002, 100 (Suppl. 1),
`139a.
`
`10. FUTURE DIRECTIONS IN THE
`TREATMENT OF TRANSFUSIONAL
`IRON OVERLOAD IN MYELODYPLASTIC
`SYNDROMES: FOCUS ON ICL670
`
`1Division of
`Jason Gotlibl and Peter L. Greenbergl'2
`Hematology, Stanford University School of Medicine,
`Stanford, California 94305; 2Palo Alto Veterans Aflairs
`Health Care System, Palo Alto, California 94304
`
`Approximately 80% of myelodysplastic syndromes
`(MDS) patients develop anemia, and many develop
`iron overload from chronic red blood cell
`(RBC)
`transfusion dependence. Evidence-based recommenda-
`tions for iron chelation in MDS are limited and are
`
`primarily derived from uncontrolled studies of patients
`with other forms of acquired anemia and transfusional
`iron overload. The advanced age of the MDS popula-'
`tion, limitations on survival due to disease evolution or
`
`co-morbidities, and the presence of organ damage re-
`lated to secondary hemochromatosis weigh heavily in
`the decision by both doctors and patients to initiate
`chelation. In MDS patients. desferrioxamine (DFO) can
`reduce iron body stores as measured by serum ferritin
`or MRI-imaging of liver iron concentration, and may
`improve cytopenias in selected patients with prolonged
`treatmentm However, subcutaneous continuous infu-
`sion of the drug using a portable pump is demanding
`and may adversely impact compliance and long-term
`efficacy. One study of 11 patients showed that twice
`daily subcutaneous bolus injection of DFO elicited
`levels of urinary iron excretion that were not statisti-
`cally different from a subcutaneous infusion of 2 grams
`over 12 hoursm In an extension phase of this study, 9
`MDS patients with ongoing RBC transfusion require-
`ments exhibited declining serum ferritin levels over 20
`months of follow-upm Although bolus DFO may be
`an option for poorly compliant individuals with MDS,
`more data are needed to evaluate efficacy in this group.
`The oral iron chelator deferiprone (Ll), approved for
`use in Europe, is generally recommended in the setting of
`clinical trials for patients with intolerance or an unsa-
`tisfactory response to DFO.[“] Potential adverse effects
`of L1 therapy include nausea/vomiting, fluctuating liver
`enzymes, anhralgias, agranulocytosis, and zinc defi-
`ciency. L1 was evaluated in a subset of patients with
`
`Dr. Reddy's Laboratories, Inc. v. Celgene Corp.
`IPR2018-01509
`Exhibit 2028, Page 5
`
`