Mirand Library
`Roswell Park Cancer Institute
`Elm & Carlton Streets
`Buffalo, NY 14263
`
`Advancements in the
`Treatment of B-Cell
`Malignancies
`
`International Conference on
`Malignant Lymphoma
`Luga no, Switzerland • June 18, 2013
`
`This activity is sponso red by th e
`Global Edu catio n Croup
`
`A CME Activity
`Approved for 1.00
`AMAPRA
`Category 1 Credit(s) 'M
`
`Release date: September 15, 2013
`Expiration date: September 15, 2014
`
`Chairman
`
`Br e D. Cheson, MD
`Deputy Chief, Hematology-Oncology
`Head of Hematology
`Lom bardi Comprehensive Cancer Center
`Geo rgetown University Hospital
`Washington, DC
`
`Faculty
`
`Jo n G. Gribben, MD, DSc,
`FM~dSci
`Professor of Medical Oncology
`Barrs Cancer lnstimce
`Queen Mary
`Unive rsity of London
`London, United Kingdom
`
`Susan O'Brien, MD
`Ashbel Smith Professor
`Department of Leukemia
`Divisio n of Cancer Medicine
`MD Anderson Cancer Center
`Houston, Texas
`
`Anure Goy, MD
`Regio nal Cancer Care Associates (RCCA)
`Chairman and Director
`Chief of Lymphoma
`Director, Clinical and Translational
`Cancer Research
`Hackensack University Medical Cenrer
`Hackensack, New Jersey
`
`This activity is supported through an
`educational grant from Pharmacyclics
`Inc.
`
`6 Pharmacyc/ics
`
`ON THE WEB:
`hematologyandoncology.net
`
`Indexed through the National Library of Medicine
`(PubMed/MEDLINE), PubMed Central (PMC), and EMBASE
`
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`

`Target Audience
`The educational design of chis activity addresses the needs of oncologists, he(cid:173)
`matologists, oncology nurses, and oncology researchers involved in the treat(cid:173)
`ment of patients with B-cell malignancies.
`
`Statement of Need/Program Overview
`Analysis of the clinical data, treatment guidelines, and ongoing clinical trials in he(cid:173)
`matology/oncology has revealed a professional practice gap in the area of those phy(cid:173)
`sicians charged with treating hematologic malignancies, including lymphoma and
`leukemia and in particular with respect to B-cell malignancies. These gaps impact
`knowledge, competence, and performance. This gap is mainly due to the current
`speed and "breakneck'' pace at which B-cell malignancies research is progressing.
`Hemarologists and oncologists find it difficult to stay apprised of the latest results
`and need direction as to how to incorporate them into clinical practice. Beyond the
`agents and technologies currently being developed, the Food and Drug Adminis(cid:173)
`tration has approved several drugs for B-cell malignancies since 2008.
`
`Educational Objectives
`After completing this activity, the participant should be better able to:
`• Describe recent advances in the current understanding of the biology of B-cell
`malignancies including aberrant cell signaling pathways.
`• Compare current and emerging treatment strategies for patients with B-cell
`malignancies.
`• Discuss evidence produced by recent studies on investigacional therapies or
`regimens for treatment of some prevalent B-cell malignancies.
`
`Faculty
`
`Chairman:
`Bruce D. Cheson, MD
`Georgerown University Hospital
`Lombardi Comprehensive Cancer Center
`Washington, DC
`
`Faculty:
`John G. Gribben, MD, DSc, FMedSci
`Barts Cancer Institute
`Queen Mary
`University of London
`London, United Kingdom
`
`Agenda
`
`Susan O'Brien, MD
`MD Anderson Cancer Center
`Houston, Texas
`
`Andre Goy, MD
`Regional Cancer Care
`Associates (RCCA)
`Hackensack University
`Medical Center
`Hackensack, New Jersey
`
`B-Cell Receptor Pathway Inhibitors(cid:173)
`Rationale and Potential
`
`lhe Changing Landscape
`in CLL
`
`For information about the accreditation of this program, please concacc GI
`at 303-395-1782 or inquire@globaleducationgroup.com
`obal
`
`Instructions to Receive Credit
`In order to receive credit for this activity, the participant muse complete th
`post program survey at https://www.surveymonkey.com/s/B-CellCAHO
`e
`
`Fee & Refund/Cancellation Policy
`There is no fee for this educational activity.
`
`Disclosure of Conflicts of Interest
`Global Education Group (Global) requires instructors, planners, manager
`and other individuals and their spouse/life partner who are in a position ts,
`control the content of chis activity to disclose any real or apparent conflict 0~
`interest they may have as related to the content of this act1v1ty. All identified
`conflicts of interest are thoroughly vetted by Global for fair balance, scientific
`objectivity of studies mentioned in the materials or used as the basis for con(cid:173)
`tent, and appropriateness of patient care recommendations.
`
`The faculty reported the following financial relationships or relationships to
`products or devices they or their spouse/life partner have with commercial in(cid:173)
`terests related to the content of chis CME activity:
`
`Name of
`Faculty or
`Presenter
`
`Bruce
`Cheson
`
`Susan
`O 'Brien
`
`Reported Financial Relationship
`
`Consultant/Independent Contractor: Celgene, Pharmacyclics,
`Teva, Merck, Seattle Genetics, Roche-Genentech; Grant/Research
`Support: Roche-Genentech, Celgene, Gilead
`
`Consultant/Independent Contractor: Celgene, Teva/Cephalon;
`Grant/Research Support: Emergent, Genentech, Gilead, Infinity,
`MorphoSys, Talon, Pharmacyclics; Speakers Bureau: lhe Medal
`Group; Other/Royalty: lhe Medal Group
`
`John
`Gribben
`
`Grant/Research Support: Celgene; Honoraria: Celgene,
`Pharmacyclics, Roche
`
`Andre
`Goy
`
`Grant/Research Support: john lheurer Cancer Center at
`Hackensack UMC; Honoraria: Celgene, Johnson & Johnson,
`Pharmacyclics; Speaker's Bureau: Millennium, Seattle Genetics
`
`The planners and managers reported the following financial relationships or
`relationships to products or devices they or their spouse/life partner have with
`commercial interests related to the content of chis CME activity:
`
`Name of Planner or Manager
`
`Reported Financial Relationship
`
`John G. Gribben, MD, DSc, FMedSci
`Barts Cancer Institute
`Queen Mary
`University of London
`London, United Kingdom
`
`Susan O'Brien, MD
`MD Anderson Cancer Center
`Houston , Texas
`
`Ashley Marostica, RN, MSN
`
`Nothing to disclose
`
`Amanda Glazar, PhD
`
`Nothing to disclose
`
`lhe Potential for Eliminating
`Chemotherapy in Indoknt
`Non-Hodgkin Lymphoma
`
`Bruce D. Cheson, MD
`Georgetown University Hospital
`Lombardi Comprehensive Cancer Center
`Washington, DC
`
`Mantle Cell Lymphoma:
`lhe Changing Landscape
`
`Andre Goy, MD
`Regional Cancer Care
`Associates (RCCA)
`Hackensack University
`Medical Center
`Hackensack, New Jersey
`
`Physician Accreditation Statement
`Global Education Group is accredired by the Accreditation Council for Continu(cid:173)
`ing Medical Education to provide continuing medical education for physicians.
`
`Physician Credit Designation
`Global Education Group designates this activity for a maximum of 1.0 AA1A
`PRA Category 1 Credit'". Physicians should claim only the credit commensurate
`with the extent of their participation in the activity.
`
`Disclosure of Unlabeled Use
`This educational activity may contain discussion of published and/or investigacional
`uses of agents that are not indicated by the FDA. Global Education Group ( -lobal)
`does not recommend the use of any agent outside of the labeled indications.
`
`The opinions expressed in the educational activity are chose of the faculty and
`do not necessarily represent the views of any organization associated with this
`activity. Please refer to the official prescribing information for each product for
`discussion of approved indications, contraindications, and warnings.
`
`Disclaimer
`Participants have an implied responsibility to use the newly acquired info rma(cid:173)
`tion to enhance patient outcomes and their own professional development.
`The information presented in this activity is not meant to serve as a guideline
`for patient management. Any procedures, medications, or other courses of di(cid:173)
`agnosis or treatment discussed in this activity should not be used by clinicians
`without evaluation of patient conditions and possible contraindications on
`dangers in use, review of any applicable manufacturer's product information,
`and comparison with recommendations of other authorities.
`
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`

`E
`
`ADVANCEMENTS IN THE TREATMENT OF B - CELL MALIGNANCIES
`
`B-Cell Receptor Pathway Inhibitors(cid:173)
`Rationale and Potential
`Joh n G. Gribben, MD, DSc, FMedSci
`
`T he B-cell receptor (BCR) pathway is fundamen(cid:173)
`
`tally important in the proliferation, survival, and
`homing of normal and malignant B cells (Figure
`1). This complex process involves numerous signaling
`molecules that are activated or inhibited as a result of
`BCR activation. Elucidation of key components of this
`pathway has identified new therapeutic targets for the
`treatment of B-cell malignancies.
`The BCR complex consists of the antigen-specific
`immunoglobulin (lg) in association with Iga/Ig~ het(cid:173)
`erodimers (CD79NCD79B). Recognition of specific
`extracellular antigens by the surface BCR activates the
`BCR signaling pathway, resulting in phosphorylation
`of the immunoreceptor tyrosine-based activation motifs
`(ITAMS) located in the intracellular domains of CD79N
`CD79B. This phosphorylation event recruits the protein
`tyrosine kinase spleen tyrosine kinase (SYK), which leads
`to the activation of the Src family kinases. This event
`results in activation of Bruton's tyrosine kinase (BTK),
`a protein that is required for BCR signaling. Activation
`of Src family kinases also results in activation of phos(cid:173)
`phoinositol-3 kinase (PI3K), which then activates the
`nuclear factor kappa-B (NF-KB) and mitogen-activation
`protein (MAP) kinase pathways.
`Targeted agents have been developed against several
`BCR-associated kinases, including SYK, BTK, and PI3K.
`Some of these agents are still in preclinical development,
`and others have demonstrated significant activity in clini-
`
`CD45
`
`CD21
`(C3d receptor)
`
`CD19
`
`The B-Cell Coreceptor
`
`Figure 1. The B-cell recepror pathway is fundamentally
`important in the proliferation, survival, and homing of normal
`and malignant B cells.
`
`cal trials. These potent agents have been shown to inhibit
`the corresponding signaling pathways and alter migration
`patterns of lymphoma cells, perhaps making them more
`susceptible to cell killing.
`
`New BCR Pathway Inhibitors
`
`Clues to the function of BTK were provided by the
`observation that individuals with a congenital deficiency
`in BTK lack B cells and antibodies. BTK is critical for
`
`Disclaimer
`Funding for chis monograph has been provided through an educational grant from Pharmacyclics Inc. Support of chis monograph does
`not imply che supporter's agreement with the views expressed herein. Every effort has been made co ensure chat drug usage and ocher
`information are presented accurately; however, the ulcimace responsibility rests wirh the prescribing physician. Millennium Medical
`Publishing, Inc., the supporter, and che participants shall not be held responsible for errors or for any consequences arising from the
`use of information contained herein. Readers are strongly urged co consulc any relevant primary literature. No claims or endorsements
`are made for any drug or compound at present under clinical investigation.
`
`©2013 Millennium Medical Publishing, Inc. , 611 Broadway, Suite 310, New York, NY 10012. Printed in the USA. All rights
`reserved, including che right of reproduction, in whole or in part, in any form.
`
`Clinical Advances in Hematology & Oncology Volume 11, Issue 9, Supplement 12 September 2013
`
`3
`
`
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
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`

`CLINICAL ROUNDTABLE MONOGRAPH --~-----
`
`lymphoma cell survival and proliferation. Several BTK
`inhibitors are being evaluated in clinical trials; the fur(cid:173)
`thest in development is ibrutinib, a tyrosine kinase inhibi(cid:173)
`tor (TKI) that forms a specific, irreversible bond with a
`cysteine reductase in BTK. 1 Ibrutinib is administered
`orally once daily. Other BTK inhibitors are being evalu(cid:173)
`ated in a twice-daily schedule in an attempt to overcome
`the synthesis of new BTK molecules within those cells.
`Ibrutinib has not demonstrated toxicity against T cells or
`natural killer cells, although off-target signaling through
`other kinases may occur.
`Ibrutinib has been shown to induce apoptosis of
`lymphoma cells. It also
`inhibits chemokine-induced
`migration of chronic lymphocytic leukemia (CLL) cells
`into the tumor microenvironment (Figure 2). 2 This
`inhibition promotes migration of CLL cells into the
`circulation, where they may be more susceptible to cell
`killing. In addition, it causes a rebound lymphocytosis
`after initial administration, which has created challenges
`for assessing responses to therapy. Although the effect of
`ibrutinib on CLL cell migration has been observed in
`both IgG-mutated and IgG-unmutated cases, clearance
`of cells from the periphery occurs more rapidly in IgG(cid:173)
`unmutated CLL, suggesting that these cells may rely more
`heavily on the tumor microenvironment for survival and
`highlighting a potential therapeutic strategy for these
`aggressive tumors. 3
`Ibrutinib has demonstrated activity in a variety of
`B-cell malignancies, including indolent non-Hodgkin
`lymphoma (NHL), CLL, and mantle cell lymphoma
`(MCL). Clinical trials are ongoing. The addition of other
`agents such as rituximab or bendamustine to ibrutinib
`has been shown to reduce the duration of lymphocytosis.
`Additional clinical trials are needed to determine whether
`a quicker response improves clinical outcomes.
`Several PI3K inhibitors in development target differ(cid:173)
`ent isoforms of this important signaling molecule. Idelalisib
`is a highly selective inhibitor of PB-kinase 8, an isoform
`that is highly restricted to lymphocytes. Idelalisib inhibits
`proliferation, induces apoptosis, and inhibits homing and
`retention of malignant B cells.4 Idelalisib has also demon(cid:173)
`strated activity in a variety of B-cell malignancies.
`PI3K inhibitors have also been developed that target
`other PI3K isoforms; these agents include a y8 inhibitor
`and pan-PI3K inhibitors. Other investigational TK.Is
`inhibit multiple pathways; one example is an inhibitor
`of PB-kinase/mammalian target of rapamycin (mTOR).
`
`150
`
`~
`
`]
`"C " ',,100
`0, .E
`l
`·x so
`"' 0
`E
`" ..c: u
`
`0
`
`(P=.055)
`
`(P=.072)
`
`(P=.059)
`
`■ PRE
`■ Day14
`■ Day28
`
`CXCL12
`
`CXCL13
`
`Figure 2. Ibrurinib inhibits chemokine-induced mi gration
`of chronic lymphocytic leukemia (CLL) cells into the rumor
`microenvironment. Adapted from Hoellenriegel J. Blood (ASH
`Ann ual MeeringAbsuacrs) 2012; 120(21) : Abstract 186.
`
`Clinical trials are needed to determine the most effective
`method of inhibiting PI3K to optimize activity against
`B-cell malignancies.
`Overall, BCR signaling inhibitors have demonstrated
`significant single-agent activity in a variety of B-cell
`malignancies, highlighting the dependence of many B-cell
`malignancies on these signaling pathways. Moreover, the
`observation that normal B cells are often less affected by
`BCR signaling inhibitors than are malignant cells suggests
`that B-cell malignancies rely on these signaling pathways
`for survival. Thus, a fuller understanding of these path(cid:173)
`ways and their dysregulation in B-cell malignancies may
`identify other potential therapeutic targets to be explored.
`
`Acknowledgment
`Dr Gribben has received grant/research support from Celgene
`and honoraria from Celgene, Pharmacyclics, and Roche.
`
`References
`
`I. Honigberg LA, Smith AM, Sirisawad M, er al. The Bruton tyrosine kinase inhibitor
`PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease
`and B-cell malignancy. Proc Nat!AcadSci USA. 2010;107(29):13075-13080.
`2. Hoellenriegel J, O'Brien S, Keating MJ, Wierda WG, Buggy JJ, Burger JA.
`In vivo inhibition of BCR activation in high-risk CLL patients on therapy with
`Bruron's tyrosine kinase inhibitor ibrutinib: correlative studies from an ongoing
`phase 2 clinical trial [ASH absrracr 186]. Blood. 2012;120(21).
`3. Byrd JC, Furman RR, Coutre S, er al. The Bruton's tyrosine kinase (BTK)
`inhibitor ibrurinib (PCI-32765) promotes high response rare, durable remissions,
`and is tolerable in treatment na'ive (TN) and 1relapsed or refractory (RR) chronic
`lymphocyric leukemia (CLL) or small lymphocyric lymphoma (SLL) patients
`including patients wirh high-risk (HR) disease: new and updated results of I 16
`parienrs in a phase lb/II srudy [ASH absrracr 189]. Blood. 2012;120(21).
`4. Lannurri BJ, Meadows SA, Herman SE, er al. CAL-101, a pl !0delra selective
`phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies,
`inhibits P13K signaling and cellular viability. Blood. 201 1; 11 7(2):591 -594.
`
`4
`
`Clinical Advances in Hematology & Oncology Volume 11, Issue 9, Supplem ent 12 September 2013
`
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`

`~~- ADVANCEMENTS IN THE TREATMENT OF B-CELL MAL I GNANCIES
`
`The Potential for Eliminating Chemotherapy
`in Indolent Non-Hodgkin Lymphoma
`
`Bruce D. Cheson, MD
`
`hemotherapy has evolved considerably since
`injectable mustard gas was first used as cancer
`therapy. Although chemotherapy has become
`more effective and, in some cases, less toxic, it is still
`associated with nonspecific effects, including acute and
`long-term toxicity. Targeted agents ' have provided an
`alternative to chemotherapy that often involves less toxic(cid:173)
`ity to healthy cells. Combinations of targeted agents have
`demonstrated activity comparable to chemotherapy or
`chemoimmunotherapy, making the possibility of chemo(cid:173)
`therapy-free regimens a potential reality.
`
`Monoclonal Antibody-Based Therapy
`
`The possibility of a chemotherapy-free regimen for indo(cid:173)
`lent lymphoma was explored nearly a decade ago , when
`Ghielmini and colleagues demonstrated prolonged remis(cid:173)
`sions with rituximab monotherapy (375 mg/m2 weekly
`fo r 4 weeks) followed by rituximab maintenance therapy
`(375 mg/m2 every 2 months for up to 4 doses) in patients
`with follicular lymphoma. 1 After a median follow-up
`of 35 months, the prolonged rituximab regimen was
`associated with a median event-free survival (EFS) of 36
`months in chemotherapy-naive patients. After 8 years,
`45% of previously untreated patients who responded to
`rituximab induction and received extended rituximab
`remained progression-free. 2
`Czuczman and colleagues conducted a phase 2 trial
`of the anti-CDSO monoclonal antibody galiximab plus
`rituximab in 61 patients with previously untreated fol(cid:173)
`licular lymphoma.3 The Follicular Lymphoma International
`Prognostic Index (FLIPI) score correlated with outcomes
`(Figure 3). The overall response rate (ORR) was 92% (75%
`complete responses [CR]) in patients with a FLIPI score of
`0 to 1, 80% (48% CR) in patients with a FLIPI score of 2,
`and 5 5% (27% CR) in patients with a FLIPI score of 3 to 5.
`After a median follow-up of 4.3 years, the median PFS was
`2.9 years, with outcomes again varying by FLIPI score. The
`regimen was well tolerated, with minimal toxicity.
`Rituximab has also been evaluated in combination
`with the anti-CD22 monoclonal antibody epratuzumab.
`In a phase 2 study of previously untreated patients with
`follicular lymphoma, 59 evaluable patients received ritux(cid:173)
`imab (375 mg/m2 weekly for 4 weeks then every 8 weeks
`for 4 additional doses) and epratuzumab (360 mg/m2
`
`0.8
`
`§ 0.6
`·-e
`0 g- 0.4
`a:
`
`0.2
`
`0 . 0 -+ - - - -~~ - -~ - - -~ - -~ - - -~ -
`o
`2
`3
`4
`Years From Study Entry
`
`-
`-
`-
`
`Low
`Intermediate
`High
`
`N= l 2
`N=25
`N=22
`
`Events=3
`Events=l 4
`Events= 17
`
`Chi-square=l 1.45
`P=.0033
`
`Figure 3. Progression-free survival by FLJPI score in the
`Cancer and Leukemia Group B 50402 srudy, a phase 2 trial of
`galiximab plus rituximab in patients with previously untreated
`follicular lymphoma. FLIPI, Follicular Lymphoma Internacional
`Prognostic Index. Adapted from Czuczman MS, et al. A11n Oncol.
`2012;23:2356-2362.3
`
`given 2 days before the first rituximab dose then on the
`same day as each subsequent rituximab dose). 4 The regi(cid:173)
`men was associated with an ORR of nearly 90% and has
`demonstrated durable responses.
`
`Antibody-Drug Conjugates
`
`Antibody-drug conjugates physically link a monoclonal
`antibody to a cytotoxic agent, providing targeted delivery
`of the cytotoxic agent directly into the target cell. The anti(cid:173)
`body-drug conjugate inotuzumab ozogarnicin consists of
`the anti-CD22 antibody linked to calichearnicin. After ino(cid:173)
`tuzumab ozogarnicin demonstrated antitumor responses in
`a phase 1 study, 5 a combination ofinotuzumab ozogarnicin
`and rituximab was evaluated in a phase 1 /2 study in patients
`with relapsed or refractory CD20-positive, CD22-positive
`B-cell NHL, including 39 patients with follicular lym(cid:173)
`phoma. Patients received rituximab plus inotuzumab every
`4 weeks for up to 8 cycles. In the subset of patients with
`follicular lymphoma, the regimen was associated with an
`ORR of 87% and a 2-year progression-free survival (PFS)
`rate of 68%. The most common grade 3/4 adverse events
`in the overall patient population were thrombocytopenia
`
`Clinical Advances in Hematology & Oncology Volume 11, Issue 9, Supplement 12 September 2013
`
`5
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`

`CLINICAL ROUNDTABLE MONOGRAPH _____ _
`
`Antigen
`lgl
`lgH
`
`I
`!
`~ [AKT]
`!
`+
`~ [mm~
`
`BTK
`
`Calcineurin
`
`i
`
`NFAT
`
`MAPK
`pathway
`
`Pl3K
`pathway
`
`NFAT
`pathway
`
`NF-KB
`pathway
`
`Figure 4. lbrutinib is a small-molecule inhibi tor of key B-cell recepror signaling pathways. Adapted from Young Rand Staudt L. Nat
`Rev Drug Discov. 2013 .21
`
`(31 %) and neutropenia (22%). Other common adverse
`events of any grade included elevated aspartate aminotrans(cid:173)
`ferase (AST; 36%) and hyperbilirubinemia (25%).
`Several other antibody-drug conjugates are currently
`in development for B-cell malignancies. Two compounds
`are being developed that use monomethyl auristatin E
`(MMAE) as the cytotoxic agent; this agent is the same one
`used in the highly active anti-CD30-containing antibody(cid:173)
`drug conjugate brentuximab vedotin. Antibody-drug con(cid:173)
`jugates under development include one linking anti-CD22
`and MMAE and another linking anti-CD79b and MMAE.
`Phase 1 studies demonstrated antitumor activity with both
`of these novel antibody-drug conjugates alone or with ritux(cid:173)
`imab in patients with relapsed/refractory B-cell NHL.6•7
`
`The ongoing randomized, phase 2 ROMULUS (A Study of
`DCDT2980S in Combination With Mab Thera/Rituxan or
`DCDS4501A in Combination With MabThera/Rituxan in
`Patients With Non-Hodgkin's Lymphoma) trial is compar(cid:173)
`ing rituximab plus the anti-CD22-containing conjugate
`versus rituximab plus the anti-CD79b-containing conju(cid:173)
`gate in patients with follicular lymphoma and diffuse large
`B-cell lymphoma. 8 Patients with a response to the assigned
`therapy remain on that therapy until disease progression,
`at which point they cross over to the other arm. Patients
`with no response to initial therapy also cross over to the
`other arm. The trial will thus evaluate the relative efficacy of
`these approaches and the potential cross-resistance of the 2
`antibody-drug conjugates.
`
`6
`
`Clin ical Advances in Hemato logy & Oncology Volume 11, Issue 9, Supplement 12 September 2013
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`

`- - - - - - - - - - - -~ ADVANCEMENTS IN THE TREATMENT OF B-CE LL MALIGNANC I ES
`
`BCR-Targeting Small-Molecule Inhibitors
`
`Event-Free Survival
`By Treatment Arm
`
`Several small-molecule inhibitors of key BCR signaling
`pathways have been evaluated alone and as components of
`combination therapy in the treatment of B-cell malignan(cid:173)
`cies. In a dose-ranging phase 1 study, the BTK inhibitor
`ibrutinib (Figure 4) demonstrated antitumor activity in
`patients with various relapsed/refractory B-cell malignan(cid:173)
`cies.9 Among the 16 enrolled patients with follicular lym(cid:173)
`phoma, single-agent ibrutinib was associated with an ORR
`of 44%, including 19% CRs, a median response duration
`of 12.3 months, and a median PFS of 13.4 months. There
`were no dose-limiting events reported. An ongoing phase 2
`study is further evaluating the efficacy and safety of ibruti(cid:173)
`nib in the treatment of follicular lymphoma.
`The PI3Ko inhibitor idelalisib (formerly CAL-101) has
`also been evaluated in the treatment ofB-cell malignancies.
`A phase 1 dose-ranging study in treatment-experienced
`patients with a variety of NHL subtypes demonstrated a
`high response rate and durable tumor control at doses of
`at least 100 mg twice daily. 10 For both ibrutinib and idelal(cid:173)
`isib, use of a dose that attains full occupancy appears to be
`important for obtaining maximal antitumor activity.
`Based on the outcomes in single-agent studies, both
`ibrutinib and idelalisib are being evaluated as components
`of combination therapy. A phase 1 study evaluating idelal(cid:173)
`isib in combination with rituximab, bendamustine, or both
`showed promising activity, with treatment up to 2.5 years
`in some patients, and no unexpected toxicities. 11 In this
`early study, the inclusion of bendamustine did not appear
`to provide additional benefit over rituximab, suggesting
`that chemotherapy could be omitted from this regimen.
`Phase 3 trials evaluating idelalisib with rituximab or benda(cid:173)
`mustine plus rituximab are under way.
`The PI3K y- o-specific inhibitor IPI-145 has also dem(cid:173)
`onstrated early activity in B-cell malignancies, including in
`patients with indolent lymphoma. 12 An expansion cohort
`is currently enrolling to further evaluate the activity and
`safety ofIPI-145 .13
`
`Agents Targeting the Apoptosis Pathway
`
`A variety of agents are also being developed that target pro(cid:173)
`teins involved in apoptosis, including BCL2 family members
`and DR4/DR5. ABT-199 is a potent, selective Bcl-2 inhibi(cid:173)
`tor that has demonstrated activity and acceptable toxicity in
`a phase 1 study of patients with relapsed NHL. 14 The best
`dose and schedule of ABT-199 have not yet been identified.
`
`lmmunomodulatory Drugs
`
`1he immunomodulatory drug lenalidomide, which is now
`approved by the US Food and Drug Administration (FDA)
`
`0.8
`
`0.6
`
`Lenalidomide plus rituximab, median 2 years
`Lenalidomide, median 1.2 years
`
`C:
`0
`
`~ 0.4
`Q_ e a.
`
`0.2
`
`0 . 0+ - - - -~ - - -~ - - -~ - - - - - : -
`2
`4
`0
`3
`Years From Study Entry
`N=45
`Events=33
`Chi-square=7.04
`N=44
`Events=21
`P=.008
`
`Arm B
`Arm C
`
`Figure 5. In th e Cancer and Leukemia Gro up B 50401 trial,
`the combination of lenalidomide plus rimxima b was assoc iated
`with improved event-free survival compared with lenalidomide
`alone. Data from Leo nard J et al. j CLin OncoL. 2010;30(15S):
`Abstract 8000 . 15
`
`for use in relapsed or refractory MCL, is also being evalu(cid:173)
`ated in a variety of other B-cell lymphomas. The random(cid:173)
`ized phase 2 Cancer and Leukemia Group B (CALGB) trial
`50401 was initially designed as a 3-arm trial comparing
`rituximab, lenalidomide, or both in patients with relapsed
`follicular lymphoma afrer at least 1 rituximab-based regimen.
`The rituximab-alone arm closed because of slow accrual, and
`results from the remaining 2 arms were presented in 2012. 15
`Of the 94 evaluable patients, 45 were assigned to lenalido(cid:173)
`mide and 44 were assigned to lenalidomide plus rituximab.
`The combination regimen appeared to be more effective
`than lenalidomide alone, with ORRs of72.7% (36.4% CR)
`and 51.1% (13.3% CR), respectively, and a median EFS of
`2.0 and 1.2 years, respectively (P=.010; Figure 5).
`The combination of lenalidomide and rituximab has
`been evaluated in other clinical trials in indolent lymphoma.
`In a phase 2, multicenter trial by Martin and coworkers in
`patients with previously untreated follicular lymphoma,
`the combination was associated with an overall response of
`92.6%, including 72.2% CRs and 20.4% partial responses
`(PRs). 16 In a single-institution study, Fowler and colleagues
`evaluated lenalidomide plus rituximab for up to 12 months
`in patients with previously untreated indolent lymphoma. 17
`The doublet therapy was associated with a high response rate,
`including 98% (87% CR) in follicular lymphoma, 89%
`(67% CR) in marginal zone lymphoma, and 80% (27%
`CR) in small lymphocytic leukemia. Although median PFS
`has not yet been reached, outcomes appear favorable.
`The international, randomized RELEVANCE (Com(cid:173)
`bined Rituximab and Lenalidomide Treatment for Untreated
`Patients With Follicular Lymphoma) trial is comparing
`rituximab plus lenalidomide induction therapy; followed by
`rituximab plus lenalidomide maintenance therapy, versus
`rituximab plus chemotherapy (investigator's choice of
`
`Clinical Advances in Hematology & Oncology Volume 11, Issue 9 , Supplement 12 September 2013
`
`7
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1008, p. 7 of 15
`
`

`

`CLINICAL ROUNDTABLE MONOGRAPH
`
`R-CHOP, R-CVP, or bendamustine plus rituximab) followed
`by rituximab maintenance. 18 This trial has the potential to
`substantially change the treatment of follicular lymphoma.
`
`Novel Combinations
`
`Early trial results with novel agents have led to the design
`of a variety of trials evaluating new combinations for the
`treatment of indolent lymphoma. The Alliance for Clini(cid:173)
`cal Trials in Oncology is sponsoring 2 studies. One trial is
`evaluating a 3-drug regimen of rituximab, lenalidomide,
`and ibrutinib (A05 l l 03) in patients with previously
`untreated follicular lymphoma. 19 The other is evaluating
`rituximab, lenalidomide, and idelalisib in relapsed/refrac(cid:173)
`tory follicular NHL patients already treated with at least
`1 anti-CD20-based regimen (A051202). 20
`In summary, approaches to the treatment of B-cell
`malignancies have been moving away from nonspecific
`cytotoxic chemotherapy toward the use of agents that spe(cid:173)
`cifically target molecules and processes important to cancer
`cell growth and survival. Although not all of these newer
`agents have significant single-agent activity, they may be
`highly effective when used in rational combinations based
`on biological mechanisms relevant to the malignancy. Thus,
`the optimal therapeutic strategy is likely to differ across
`lymphoma subtypes, which tend to be biologically hetero(cid:173)
`geneous. Therapy will likely become more individualized.
`With the number of agents under active investigation, it
`will be important to accrue sufficient numbers of patients
`on clinical trials to fully evaluate these agents. These strat(cid:173)
`egies may lead to the elimination of chemotherapy, in at
`least some cases, and increase the potential for cure.
`
`Acknowledgment
`Dr Cheson is a consultant/independent contractor for Cel(cid:173)
`gene, Pharmacyclics, Teva, Merck, Seattle Genetics, and
`Roche-Genentech. Dr Cheson has received grant/research
`support from Roche-Genentech, Celgene, and Gilead.
`
`References
`
`1. Ghielmini M, Schmitz SF, Cogliatti SB, et al. Prolonged treatment with rirux(cid:173)
`imab in patients with follicular lymphoma significantly increases event-free survival
`and response duration compared with the standard weekly x 4 schedule. Blood.
`2004; I 03(12):4416-4423.
`2. Martinelli G, Schmitz SF, Utiger U, et al. Long-rerm follow-up of patients with
`follicular lymphoma receiving single-agent rituximab at two different schedules in
`trial SAKK 35/98.J Clin Oncol. 2010;28(29):4480-4484.
`3. Czuczman MS, Leonard JP, Jung S, et al. Phase II trial of galiximab (anti-CD80
`monoclonal antibody) plus rituximab (CALGB 50402): Follicular Lymphoma
`Incernarional Prognostic Index (FLIPI) score is predictive of upfront immuno(cid:173)
`therapy responsiveness. Ann Oncol. 2012;23(9):2356-2362.
`
`4. Grant BW, Jung SH , Johnson JL, et al. A phase 2 trial of extended induction
`epraruzumab and riruximab for previously uncreated follicular lymphoma: CALGB
`50701. Cancer. 2013 Aug 6. doi: 10.1002/cncr.28299. [Epub ahead of print]
`5. Advani A, Coiffier B, Czuczman MS , et al. Safety, pharmacokinetics, and pre(cid:173)
`liminary clinical activity ofinocuzumab ozogamicin, a novel immunoconjugate fo r
`the treatment ofB-cell non-Hodgkin's lymphoma: results of a phase I study.] Clin
`Onco/. 2010;28(12):2085-2093.
`6. Advani R, Chen A, Lebovic D , et al. Phase I study of the anti-CD22 antibody(cid:173)
`drug conjugate (ADC) DCDT2980S with or without rituxirnab (RTX) in patients
`(pts) with relapsed or refractory (R/R) B-cell non-Hodgkin's lymphoma (NHL)
`[ICML