NETaa aSSRECAC AONE
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Application of: Jerome B. Zeldis
`
`Group Art Unit: 1629
`
`Serial No.: 12/621,502
`
`Confirmation No.: 2588
`
`Filed: November 19, 2009
`
`Examiner: Anderson, James D.
`
`For: METHODS USING 3-(4-AMINO-1-OX0-1,3- Attorney Docket No.: 9516-904-999
`DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-
`DIONE FOR TREATMENT OF MANTLE CELL
`LYMPHOMAS
`
`DECLARATION BY LEL ZHANG, M.D. UNDER 37 C.F.R. 1.132
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`I, Lei Zhang, M.D., declare and state that:
`
`1,
`
`I recerved my M.D. degree from the Capital Medical University in Beijing, China,
`
`and a M.S. degree in biochemistry at Medical College of Virginia, Virginia Commonwealth
`
`University, Richmond, Virginia.
`
`2,
`
`Following completion of my medical degree, ] was trained as a staff physician in
`
`internal medicine, including the diagnosis and treatment of hematologic malignancies.
`
`I later
`
`worked at several major pharmaceutical companies in their clinical development and regulatory
`
`submission divisions, with an emphasis on oncology drugs.
`
`[ joined Celgene Corporation,
`
`Summit, New Jersey in 2008.
`
`I am presently a Executive Director and Clinical Research
`
`Physician of Celgene Corporation, and I am responsible for its oncology clinical research and
`
`development in the lymphoma program.
`
`[ have been the lead physician in Celgene
`
`Corporation’s global regulatory submission team in Mantle Cell Lymphoma (“MCL”)
`
`registration program.
`
`| have overseen the clinical and scientific activities in key global
`
`registration studies of lenalidomide in MCL treatment. A copy of my curriculum vitae is
`
`enclosed herewith.
`
`Apotex Ex. 1008, p. 1
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`Apotex Ex. 1008, p. 1
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`

`

`nn SSERATa"SESSetSSISAs PNiscnt
`
`3.
`
`Lam familiar with the disclosure and claims ofthe above-identified patent
`
`application (“the ‘502 application”).
`
`[ understand that the pending claimsare directed to, inter
`
`alia, methods of treating MCL with about 5 mg to 25 mg per day of 3-(4-amino-1-oxo-1,3-
`
`dihydro-isoindol-2-yl)-piperidine-2,6-dione(7.e., lenalidomide) orits salt or hydrate. The
`
`compound lenalidomide is administered for a period of time followed by a period of rest.
`
`[ also
`
`understand that in an Office Action issued on September 19, 2013 by the Patent Office, the
`
`pending claims are rejected under 35 U.S.C. § 103(a) as allegedly being unpatentable over Zeldis
`
`(U.S. Publication No. 2004/0029832 A1) in view of secondary references Damaj etal.
`
`(Leukemia, 2003, vol. 17, pages 1914-1915; “Damaj”), Wilsonet al, (British J. ofHaematology,
`
`2002, vol. 119, pages 128-130; “Wilson”), and Kaufmann ef al. (Blood, 2004, vol. 104, no. 8,
`
`pages 2269-2271; “Kaufmann’”).
`
`+.
`
`[have reviewedthe cited references including Damaj, Wilson and Kaufmann. It
`
`is my opinion that oneofordinary skill in the art would not have concluded based on the
`
`disclosure of these references that the compound thalidomide would be therapeutically effective
`
`in treating MCL. Damaj reported two individual MCL patients treated with thalidomide. Wilson
`
`reported the case of a single MCL patient. To determine whether an agentis therapeutically
`
`effective in treating a certain disease, one ofordinary skill in the art would have needed a
`
`statistically significant amount of evidence, including preclinical safety and toxicity information.
`
`The evidence presented in Damaj and Wilsonis limited to three individual patients and is clearly
`
`insufficient. While Kaufmann evaluated a combination strategy using thalidomide and rituximab
`
`in 16 patients and reported that 13 patients achieved objective responses, only 3 of these patients
`
`were previously treated with rituximab, an agent that was knownto inhibit MCLatthe time of
`
`Kaufmann’s study. As such, it cannot be ascertained whether the response observed in the 13
`
`patients was induced byrituximab, thalidomide, or their combination. Therefore, it is my
`
`opinion that one of ordinary skill in the art would not have concluded that thalidomide is
`
`therapeutically effective in treating MCL based on these three references. Additionally, | am not
`
`aware of anylarge-scale clinical study of thalidomide in treating MCL that was conducted
`
`following the publication ofthese references.
`
`5.
`
`There is a significant unmet need in therapeutic options for MCLpatients, in
`
`particular those with relapsed, refractory, or relapsed and refractory MCL.
`
`In spite of improved
`
`Apotex Ex. 1008, p. 2
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`Apotex Ex. 1008, p. 2
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`

`

`treatment options for MCL patients, MCL continues to have the poorest prognosis among non-
`
`Hodgkin’s lymphoma (NHL) subtypes. With each successive relapse, MCL patients experience
`
`chemo-resistance and shorter duration of response. The overall survival for relapsed or
`refractory MCL is estimated to be only 1-2 years. Prior to June 2013, bortezomib (Velcade *)
`was the only drug approved by the U.S. Food and Drug Administration (“FDA”)for patients
`
`with relapsed or refractory MCL. Oncethepatients relapse after or fail the bortezomib
`
`treatment, no clear treatment option is available.
`
`6.
`
`[ was the lead clinician in the PhaseII study of lenalidomide in MCL treatment.
`
`|
`
`am familiar with both the compound lenalidomide andits therapeutic effects in MCL patients.
`
`All patients enrolled in this study were heavily pretreated for MCL (median numberofprior
`
`treatments is 4) and 93% of the patients had stage [I-IV MCL.
`
`In addition, all patients had
`
`received prior treatment with bortezomib. Lenalidomide, when administered as described in the
`
`claims, achieved an overall response rate of 28%(central review)/32% (investigator review),
`
`including a complete responserate of 7.5%(central review)/16% (investigator review). The
`
`median duration of response is 16.6 months (central review)/18.5 months (investigator review).
`
`The median duration of response tor complete response is 16.6 months (central review)/26.7
`
`months(investigator review). Also significantly, with a median follow-up of 9.9 months,
`
`median overall survival is 19.0 months. Theresults of the Phase II study are described in the
`
`Goyef al. (2013) article enclosed herewith. The safety profile of lenalidomide in these patients
`
`was also manageable.
`
`7.
`
`It is my opinionthatthe efficacy oflenalidomide in relapsed, refractory, or
`
`relapsed and refractory MCL demonstrated in this study would have been unexpected and
`
`surprising at the time the claimed invention was made,particularly in view of the unfavorable
`
`prognosis ofthe patients. The FDA granted fast track designation to lenalidomide based onits
`
`activity and tolerability in heavily pretreatment relapsed or refractory MCL patients who
`
`received prior bortezomib therapy, and approved lenalidomide for this indication based on the
`
`Phase II study results.
`
`8,
`
`[ hereby declare that all statements made herein of my own knowledgeare true
`
`and that all statements made on information and beliefare believed to be true; and further that
`
`fs
`
`Apotex Ex. 1008, p. 3
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`Apotex Ex. 1008, p. 3
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`

`

`AeaSEESIITSSSoi te sist
`
`these statements were made with the knowledge that willful false statements and the like may be
`
`punishable by fine or imprisonment, or both, under Section 1001 of Title 18 ofthe United States
`
`Code, and that such willful false statements may jeopardize the validity of any patent issuing
`
`from the present application.
`
`eed 1S, 20/2C>
`
`Dated:
`
`Lei Zhang, M.D.
`
`Apotex Ex. 1008, p. 4
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`Apotex Ex. 1008, p. 4
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`

`

`
`
`
`
`Exhibit A
`
`Apotex Ex. 1008, p. 5
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`Apotex Ex. 1008, p. 5
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`

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`
`
`CURRICULUM VITAE
`Lei Zhang, M.D.
`
`Celgene Corporation
`86 Morris Avenue
`Summit, NJ 07901
`lei_zhang@celgene.com (work)
`
`PROFILE
`
`®
`
`e
`
`e
`
`«
`
`Clinical Research Physician responsible for oncology medical monitoring with
`extensive therapeutic knowledge of oncology/general medicine, excellent
`management and communication skills.
`Clinical research professional with 15+ years in the pharmaceuticals industry, and
`molecular biology research
`Extensive experience in designing and managing oncologyclinical trials (phase I-
`IV, including large global phase III registration study, both in hematological
`malignancies and solid tumors)
`Strong regulatory registration expertise with significant contributions in several
`registration programs in career
`
`PROFESSIONAL EXPERIENCE:
`
`November 2008 — Present, Celgene Corporation, Summit, New Jersey
`Senior Medical Director, Clinical Research Physician,
`Oncology Clinical R & D, Lymphoma Program — Lenalidomide, Romidepsin and BTK inhibitor
`CC292
`
`e
`
`Lead physician for global regulatory submission team in Mantle Cell Lymphomaregistration
`program. Lead author of key sNDA documents including pivotal trial study report, Intergraded
`Summary of Efficacy, Intergraded Summary of Safety, and Clinical Overview in filing dossier.
`* Oversee the clinical and scientific activities in key global registration studies including Mantle Cell
`Lymphoma & Diffuse Large B cell Lymphomastudies in Lenalidomide Lymphoma Program.
`Provide leadership to clinical study team in the execution ofclinical studies
`Develop clinical strategy in lymphoma program
`Design phase II and phase III clinical study protocol, manage the studies as medical monitor.
`Interactions with Key Opinion Leaders in lymphoma field worldwide.
`Interactions with health authorities both in the US and Europe.
`
`August 2004 — November 2008, Novartis Pharmaceuticals Corporation, Florham Park, New Jersey
`Clinical Research Physician, Oncology Global Development
`2004 — 2006
`PKC412 Program, AML, MDS,and GISTindications
`2006 — 2008
`LBH589 (Panobinostat, HDAC inhibitor) Program , Hodgkin and non-Hodgkin
`lymphoma indications
`
`*
`
`*
`
`*
`
`e
`
`*
`
`Developed global clinical strategy and clinical development plan ofproject in global Phase III
`registrationtrial.
` Oversawall clinical development activities as clinical indication leader for multiple indications
`including leukemia, MDS, GIST, Hodgkin and non-Hodgkin lymphoma.
`Primary responsibility for the protocol development, medical monitoring, and clinical study report
`for all trials
`
`Primary responsibility for the LBH589 health authority activities in lymphomaindication. Primary
`author of regulatory documents, such as briefing books, successful Orphan Applications in US and
`EU (granted from both FDA and EMEA/COMP),pediatric waiver request in EU (granted from
`EMEA/PDCO)
`Represented clinical atHA meetings, including end of Ph II meeting w/FDA, SPA meeting with
`FDA, scientific advice meeting with EMEA/SAWP (Scientific Advice Working Party), etc.
`
`Apotex Ex. 1008, p. 6
`
`Apotex Ex. 1008, p. 6
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`

`

`e=Collaborated with internal multi-functional teams, external Key Opinion Leaders, and CROs.
`e
`Direct reports included 8 FTEs both in US and Switzerland
`
`1998 — Aug 2004, Eli Lilly and Company, Indianapolis, Indiana
`Senior Clinical Development Scientist, Oncology Global Team
`
`o
`
`e
`
`e
`
`e
`
`Regulatory Submission/Registration Expertise
`©
`Significant contributions to the successful ALIMTA™ Mesothelioma and Non-small Cell
`Lung Cancer NDA filing as key submission team member
`Experienced in global (US and EV)registration process, such as NDA submission
`document preparation, regulatory query responses, FDA audit, etc.
`o Coordinated the preparation activity for FDA ODAC meeting
`Recognized expert for the breadth of clinical trial development knowledge, making high-value
`contributions on projects
`©
`Experienced in all phases of drug development, from early phase | development, phaseII
`study, to large global phase III registration study, and post-marketing phase IV study.
`o Ultimately worked with all aspectsin clinical trials, from protocol development, study
`start-up phase to database lock, final study report writing and publications.
`Indications included Lung, Methothelioma, Gastric and Colorectal Cancers
`©
`Responsible for Annual IND safety reports and IB
`o
`Other activities include:
`o
`Safety monitoring, safety review and analysis
`CRF development, clinical data review
`Managedstudy timeline and budget.
`CRO management. Setup the first ALIMTAcollaboration trial with NSABP
`Effective liaison between global team and Japan leading to the successful Kiko meeting
`and ALIMTAfirst human dose in Japan
`People management
`Initiated and led the development of cross function on-board training program. Led the
`SOP review and implementation process. Active members of Oncology Protocol Review
`Committee, Oncology SOP Review Committee, Study Development Process
`Optimization Working Group, Clinical Preceptor Program
`
`ooo°0
`
`ao0
`
`1997 — 1998, Hoffmann-La Roche, Diagnostics Corp. USA, Indianapolis, Indiana
`Research Scientist, Roche Diagnostics Corp. USA
`Preclinical research in immunology, recombinant protein expression and purification
`
`1994 — 1997, Medical College of Virginia, Richmond, Virginia
`Research Scientist, Division of Biochemistry and Molecular Biology
`« Molecular biology research
`e
`Experimental design, protocol development and data analysis
`
`1986 — 1990, Beijing Tiantan Hospital, Division of Internal Medicine, Beijing, China
`Staff Physician, Division of Internal Medicine
`
`Diagnosis and treatment of internal medicine diseases, including cardiovascular, endocrine, respiratory, GI,
`and hematologic disorders including coagulation disorders, hematologic malignancies such as acute
`leukemia, myeloproliferative disorders (e.g. chronic myeloid leukemia), lymphoproliferative disorders
`(Hodgkin lymphoma, non-Hodgkin lymphomas), and plasmacell dyscrasias ( e.g. multiple myeloma).
`
`EDUCATION
`M. D. Capital Medical University, Beijing, China, 1986
`M.S. Biochemistry, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA
`1994
`
`PROFESSIONAL MEMBERSHIP
`
`American Society of Clinical Oncology
`American Society of Hematology
`American Association for Cancer Research
`
`Apotex Ex. 1008, p. 7
`
`Apotex Ex. 1008, p. 7
`
`

`

`EAROS ANealGS
`
`
`
`ACHIEVEMENT AWARDS
`
`Oncology Global Development Vision Award, Excellence in Execution, June 2008, Novartis Oncology
`Passion, Quality, and Speed Award, November 2005, Novartis Oncology
`Technical Excellence Award for Successful ALIMTA® NSCLC ODAC Meeting, August 2004, Eli Lilly &
`Company
`Scientific/Clinical Contribution Award, Corporate Clinical Development, February 2004, Eli Lilly &
`Company
`Individual Leadership Award in Customer Relationship Management Award, Corporate Summit and
`Recognition Event, February 2002, Eli Lilly & Company
`
`PUBLICATIONS
`
`A. Goy, R. Sinha, M. E. Williams, S. K. Besisik, J. Drach, R. Ramchandren, M. J. Robertson, I. Avivi, J.
`M. Rowe, R. Herbrecht, A. Van Hoof, M. Egyed, L. Zhang, S. Cicero, T. Fu, and T. Witzig. Phase I]
`Multicenter Study of Single-Agent Lenalidomide in Subjects With Mantle Cell Lymphoma Who Relapsed
`or Progressed After or Were Refractory to Bortezomib: The MCL-001 Study (EMERGE™Trial). Blood
`(ASH Annual Meeting Abstract) 2012 Abstract # 905
`
`P. Zinzanil, J. Vose, M. S. Czuczman, C. B. Reeder, C. Haioun, J. Polikoff, L. Zhang, K. Prandi, J. Li,
`and T.E. Witzig. Phase I] Multicenter study of the Safety and Efficacy of Single-agent lenalidomide in
`Patients with Relapsed/Refractory mantle Cell Lymphoma: Long-term Follow-up Analysis of the NHL-003
`Study. Blood (ASH Annual Meeting Abstract) 2012 Abstract# 2738
`
`M. Duvicl, J.C. Becker, 8. Dalle, F. Vanaclocha, M. G. Bernengo, C. Lebbé, R. Dummer, S. Hirawat, L.
`Zhang, M. Marshood,G. Laird and H. M. Prince. Phase II Trial of Oral Panobinostat (LBH589)in Patients
`with Refractory Cutaneous T-Cell Lymphoma (CTCL). Blood (ASH Annual Meeting Abstracts) 2008 112:
`Abstract # 1005
`
`L. Zhang, D, Lebwohl, E. Masson, G. Laird, M.R. Cooper, H.M. Prince. Clinically relevant QTC
`prolongation is not associated with current dose schedule of LBH589 (panobinostat). JCO, Vol 26, No. 2,
`2008: 332-333
`
`M. Duvic, F. Vanaclocha, M. G. Bernengo, C. Okada, D. Breneman, P. L. Zinzani, L. Zhang, K. Bopp, G.
`Laird, 8. Hirawat, M. Prince. Phase II study of oral panobinostat (LBH589), a potent pan-deacetylase
`inhibitor, in patients with refractory Cutaneous T-cell Lymphoma (CTCL). Abstract #8555, ASCO 2008
`
`M.G. Bernengo, F. Vanaclocha, M. Duvic, T. Kuzel, F. Kerdel, L. Pinter-Brown, A. Bosly, C. Okada, D.
`Breneman, P. Zinzani, J. Becker, L. Hughey, M. Ardaiz, J. Zain, L. Zhang, M. Marshood, K. Bopp, S.
`Hirawat, G Laird!, D. Johnson, H.M. Prince. Phase [I Study of Oral Panobinostat (LBH589), a Potent Pan-
`Deacetylase Inhibitor, in Patients with Refractory Cutaneous T-Cell Lymphoma (CTCL). Abstract # 1279,
`EHA 2008
`
`F. Vanaclocha, M.G. Bernengo, J. C. Becker, M. Duvic, L. Pinter-Brown, J. Zain, L. Zhang, S. Hirawat,
`G, Laird, H. M. Prince. Phase II trial of oral panobinostat (LBH589) in patients with refractory cutaneous
`T-cell lymphoma. ESMO 2008
`
`T. Fischer, F. Giles, R. Paquette, G. Schiller, G. Ehninger, C. Schiffer, J. Cortes, H. Kantarjian, D.
`DeAngelo, F. Heidel, P.S. Cohen, R. Yu, S. Bilic, L. Zhang, P. Phillips and R.M. Stone. Phase IB Study of
`PKC412, an Oral FLT3 Kinase Inhibitor, in Sequential and Simultaneous Combinations with Daunorubicin
`and Cytarabine (DA) Induction and High-Dose Cytarabine Consolidation in Newly Diagnosed Patients with
`AML. 2006 EHA, abstract #0977
`
`P. Reichardt, D. Pink, T. Lindner, M. C. Heinrich, P. S. Cohen, L. Zhang, Y. Wang, R. Yu, A. Tsyrlova,S.
`Dimitrijevic, C. Blanke. A phase I/II trial of the oral PKC-inhibitor PKC412 (PKC) in combination with
`imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM. Journal
`of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of I] (June |
`Supplement), 2005: 3016
`
`Apotex Ex. 1008, p. 8
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`Apotex Ex. 1008, p. 8
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`

`

`R. M. Stone, T. Fischer, R. Paquette, G. Schiller, C. A. Schiffer, G. Ehninger, J. Cortes, H. Kantarjian, D.
`A. DeAngelo, R. Yu, L. Zhang, P.S. Cohen, Y. Wang, P. Phillips and F. Giles. Phase IB study of PKC412,
`an oral FLT3 kinase inhibitor, in sequential and simultaneous combination with daunorubicin and
`cytarabine (DA) inductin and high dose cytarabine consolidation in newly diagnosed patients with AML.
`Blood, Vol 106, No. 11, 2005: 12 1a, abstract # 404
`
`
`
`Apotex Ex. 1008, p. 9
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`Apotex Ex. 1008, p. 9
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`

`

`
`
`Exhibit B
`
`Apotex Ex. 1008, p. 10
`
`Apotex Ex. 1008, p. 10
`
`

`

`
`
`
`Published Ahead of Print on September3, 2013 as 10.1200/JCO.2013.49.2835
`Thelatest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JC0.2013.49.2835
`
`
`
`Single-Agent Lenalidomide in Patients With Mantle-Cell
`Lymphoma WhoRelapsedor Progressed After or
`WereRefractory to Bortezomib: Phase II MCL-001
`(EMERGE)Study
`Andre Gay, Rajni Sinha, Michael E. Williams, Sevgi Kalayoglu Besisik, Johannes Drach,
`Radhakrishnan Ramchandren, Lei Zhang, Sherri Cicero, Tommy Fu, and Thomas E, Witzig
`
`Listen to the podcast by Dr Till at www.jco.org/podcasts
`2
`kes 81 A er
`
`Purpose
`Although dose-intensive strategies or high-dose therapy induction followed by autologous
`stem-cell transplantation have improved the outcome for patients with mantle-cell
`lymphoma
`(MCL), most eventually relapse and subsequently respond poorly to additional therapy. Bort-
`ezomib (in the United States) and temsirolimmus (in Europe) are currently the only two treatments
`approved for relapsed disease. Lenalidomide is an immunomodulatory agent with proven
`tumoricidal and antiproliferative activity in MCL. The MCL-001 (EMERGE)
`trial
`is a global,
`multicenter phase II study examining the safety and efficacy of lenalidomide in patients who had
`relapsed or were refractory to bortezomib.
`Patients and Methods
`Lenalidomide 25 mg orally was administered on days 1 through 21 every 28 days until disease
`progression or intolerance. Primary end points were overall response rate (ORR) and duration of
`response (DOR); secondary end points included complete response (CR) rate, progression-free
`survival (PFS), overall survival (OS), and safety.
`Results
`In all, 134 patients were enrolled with a median age of 67 years and a median of four prior
`therapies (range, two to 10 prior therapies). The ORR was 28% (7.5% CR/CR unconfirmed) with
`rapid time to response (median, 2.2 months) and a median DOR of 16.6 months (95% Cl, 7.7 to
`26.7 months). Median PFS was 4.0 months (95% Cl, 3.6 to 5.6 months), and median OS was 19.0
`months (95% Cl, 12.5 to 23.9 months). The most common grade 3 to 4 adverse events were
`neutropenia (43%), thrambocytopenia (28%), anemia (11%), pneumonia (8%), and fatigue (7%).
`Conclusion
`The MCL-001 study demonstrated durable efficacy of lenalidornide with a predictable safety
`profile in heavily pretreated patients with MCL who had all relapsed or progressed after or were
`refractory to bortezomib.
`
`Andre Goy, John Theurer Cancer
`Center at Hackensack University Medi-
`cal Center, Hackensack; Lei Zhang,
`Sherri Cicero, and Tommy Fu, Celgene,
`Summit, NJ: Rajni Sinha, Emory Univer-
`sity Winship Cancer Institute, Atlanta,
`GA; Michael E. Williams, University of
`Virginia Health System, Charlottesville,
`VA; Sevgi Kalayoglu Besisik, Istanbul
`University Faculty of Medicine, Istanbul,
`Turkey; Johannes Drach, Medical
`University of Vienna, Vienna, Austria;
`Radhakrishnan Ramchandren, Karma-
`nos Cancer Institute, Detroit, MI: and
`Tharmas E. VVitzig, Mayo Clinic,
`Rochester, MN.
`Published online ahead of print at
`wwiw.joo.org on September 3, 2013.
`Supported by Celgene.
`Presented in part at the S4th American
`Society of Hematology Meeting and
`Exposition, Atlanta, GA, December
`8-11, 2012.
`Authors’ disclosures of potential con-
`flicts of interest and author cantribue
`tions are found at the end of this
`article.
`Clinica! trial information: NCTOO?37529.
`
`Corresponding author: Andre Goy, MD,
`John Theurer Cancer Center at Hacken-
`sack Unwersity Medical Center, 20
`Prospect Ave, Hackensack, NJ 07601;
`J Clin Oncol 31. © 2013 by American Society of Clinical Oncology
`e-mail: agoy@humed.com.
`® 2013 by American Society of Clinical
`ars
`Oncology
`Combination chemotherapy and immuno-
`
`
`
`0732-183X/13/3199-1/$20.00
`therapy is the foundation of first-line MCL treat-
`Mantle cell lymphoma (MCL)is an uncommon
`DO!: 10.1200/JCO.2013 49.2836
`ment and, when feasible, dose-intensive/induction
`subtype of non-Hodgkin lymphoma (NHL),'ac-
`strategies followed by high-dose therapy and au-
`counting for 3% to 6% of NHL,?* Median age at
`tologous stem-cell
`transplantation (HDT-ASCT)
`consolidation have improved outcomes.*'''° Al-
`diagnosis is mid to late 60s and patients typically
`present with advanced-stage disease.”*? Al-
`ternative optionsin older patients or those with co-
`though overall survival (OS) has improved over
`morbidities include less intensive strategies (eg,
`the last two decades, MCL remains challenging,
`bendamustine plus rituximab), some of which may
`incorporate maintenance strategies to improve du-
`especially in the relapsed/refractory setting in
`ration of disease control.?’*"* Following relapse,
`which median OS is approximately |
`to 2 years
`with current therapies.*'°
`there are limited options, with minimalbenefit from
`
`© 2013 by American Society of Clinical Oncology
`Information downloaded from jco.ascopubs.org and provided by at Celgene on September 4, 2013 from 216.118.82.254
`Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
`Copyright 2013 by American Society of Clinical Oncology
`
`1
`
`Apotex Ex. 1008, p. 11
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`Apotex Ex. 1008, p. 11
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`

`
`
`ta EATR SE
`
`
`Goy et al
`
`standard chemotherapy or HDT-ASCT,because patients often be-
`come chemotherapy resistant.'>'*?° Two therapeutic agents are
`currently approvedin the relapsed/refractory setting: bortezomib
`(a proteasomeinhibitor; United States) and temsirolimus (a mam-
`malian target ofrapamycin complex 1 inhibitor; Europe).7'7? Both
`are limited by intravenous administration and short duration of
`response (DOR),??°77 substantiating the need for novelalternatives
`for these patients.
`Lenalidomide (Revlimid; Celgene, Summit, NJ) is an immuno-
`modulatory agent initially studied in multiple myeloma and myelo-
`dysplastic syndromes.***! Preclinical studies showed antitumor and
`antiproliferative activities in leukemia and lymphoma,
`including
`MCL.**? Twophase II studies (NHL-002 and NHL-003) reported
`clinical activity of lenalidomide in heavily pretreated patients with
`relapsed/refractory aggressive NHL,*°"*° including MCL.*7"" With a
`similar dosing schema (25 mg per day orally for 21 of 28 days),
`responses were consistent between studies, including 35%overall
`response rate (ORR) for both (12% to 13% complete response [CR]),
`median DOR of6.2 months (NHL-002) and 10.6 months {NHL-003),
`and medianprogression-free survival (PFS) of4.0 months (NHL-002)
`and 3,7 months (NHL-003) acrossall histologies.*>** Interestingly,
`higher and more durable responses were seen in MCL versus other
`NHLsubtypes. Patients with MCL in NHL-002 showed 53% ORR
`(20% CR), median DOR of 13.7 months, and median PFS of 5.6
`months.” Central review in the NHL-003 study showed 35% ORR
`(12% CR/ CR unconfirmed [CRu]), median DOR of 16.3 months,
`and median PFS of 8.8 months.** Responses were independent of
`baseline characteristics or prior therapies; most commongrade 3 to 4
`adverse events (AEs) for patients with MCL in NHL-002 and NHL-
`003 were neutropenia (40% and 46%) and thrombocytopenia (33%
`and 30%), respectively.*”** On the basis of these encouraging results
`and limited treatmentoptions in relapsed/refractory MCL, the MCL-
`001 (EMERGE)phaseII study wasdesigned to examinethe safety and
`efficacy of single-agent lenalidomide in heavily pretreated patients
`whohadrelapsed, progressed, or were refractory to bortezomib.
`
`
`
`Patients
`Theinstitutional review board or independentethics committee at each
`participating institution reviewed and approved the study protocol, amend-
`ments, andpatient's written informed consent before studyinitiation. Study
`design and conduct were in accordance with ethical principles of Good Clini-
`cal Practice accordingto International Conference on Harmonization Har-
`monized Tripartite Guidelines and the Declaration of Helsinki.
`Keyinclusion criteria were confirmed MCL diagnosis with cyclin-D1
`overexpression by immunchistochemistry ort(11;14)(q13;q32) translocation
`byfluorescentin situ hybridization, age =18 years, Eastern Cooperative On-
`cology Group (ECOG) performancescore 0 to 2, absolute neutrophil count
`= 1,500/aL,platelets = 60,000/uL, and adequate organfunction. Diagnosis
`criteria included measurable lesion (= 2 cm by computed tomography [CT]).
`Patients were requiredto have prior anthracycline or mitoxantrone, cyclophos-
`phamide,or rituximab therapy and documented relapsed,refractory, or pro-
`gressive disease (PD) following bortezomib (alone or in combination). The
`definition of relapse was within | year of the last dose of bortezomib and
`following aninitial CR to a bortezomib-containing regimen. Refractory to
`bortezomib was defined as PD without achieving atleast a partial response
`(PR) during treatment after at least two cycles of a bortezomib-containing
`regimen. PD was within | year ofthe last dose of bortezomib after achiev-
`ing a PR to a bortezomib-containing regimen. Patients whorelapsedafter
`
`HDT-ASCTwereeligible, and there was no limitation for the number of
`prior therapies.
`Key exclusioncriteria included the presence of CNS disease, creatinine
`clearance (CrCl) < 30 mL/min,eligibility for HDT-ASCT orallogeneic stem-
`cell transplantationper investigator decision, corticosteroids = 1 week (> 10
`mg per day prednisone or equivalent), unwillingness to receive contraception
`or prophylaxis for deep vein thrombosis, desquamating rash with prior
`thalidomide, prior exposure to lenalidomide, chemotherapy = 2 weeks,
`nitrosourea = 6 weeks, monoclonal antibody = 8 weeks, radioimmuno-
`conjugate = 12 weeks, or external radiotherapy = 3 weeks.
`Study Design
`MCL-001 (EMERGE; NCT00737529) was a global, multicenter, single-
`arm, open-label phase II study ofsafety andefficacy of single-agent lenalido-
`mide in patients who had relapsed, progressed, or were refractory to
`bortezomib, Primary end points were ORR and DOR; secondary end points
`included safety, CR/CRu,time to response (TTR), time to progression (TTP),
`timeto treatmentfailure (TTF), PFS, and OS.
`Lenalidomide 25 mg (10 mg for CrCl = 30 to < 60 mL/min) was
`self-administered orally on days | through 21 of each 28-day cycle until PD,
`intolerance, or voluntary withdrawal, Dosing was based on prior NHL studies
`(including MCL)**” and approved dosing in multiple myeloma.*?
`Dose modification/interruption was planned in the event of grade = 2
`allergic reaction or hypersensitivity; > 3% upperlimit ofnormal AST, ALT,or
`bilirubin; grade | or higher tumorlysis syndrome (TLS; by Cairo-Bishop
`grading system");sustained grade = 3 neutropenia for = 7 days or associated
`with fever (= 38.5°C); thrombocytopenia (platelets < 50,000/wL); constipa-
`tion; desquamating(blistering) rash (or grade 4 nondesquamating rash); ve-
`nous thrombosis/embolism; new peripheral neuropathy; tumorflare reaction
`(TFR); or lenalidomide-related nonhematologic AE. Allopurinol 300 mg per
`day or equivalent was recommended for TLS prophylaxis with oral hydration
`duringthefirst 7 days of treatment(or as indicated). Patients at high-risk for
`developing a thromboembolic event(TEE;defined as a history of TEE and/or
`concomitant medication with increased risk and/or known hypercoagulable
`state regardless of thromboembolic history) received prophylaxis (eg, aspirin
`70 to 100 mg per day, low-molecular-weight heparin [LMWH], or wartarin,
`per investigator). Growth factors were not administered as prophylaxis but
`were allowed to treat severe hematologic events. Concomitant anticancer
`therapy was prohibited, although physiologic doses ofsteroids (= 10 mg per
`day) not prescribed for MCL were permitted.
`Response and Safety Assessments
`Safety assessments included AEs, pregnancy tests for females of child-
`bearing age, second primary malignancies (SPMs), TLS, and TFR, hematol-
`ogy, serum chemistry, and other laboratory tests. CT scans were performed
`every two cycles (+ 7 days) throughouttreatment and every 90 days (+ 14
`days) after stopping lenalidomide until progression orinitiation ofsubsequent
`antilymphomatherapy. Confirmatory bone marrow aspirate and unilateral
`biopsy was required within 28 days for patients achieving CR (by CT).
`Efficacy analyses were performed inthe intent-to-treat patient popula-
`tion as defined in the protocol. Response data were evaluated by investigators
`and an independentreview committee (ie, central review) per modified Inter-
`national Workshop Lymphoma Response Criteria.’*"!'“"* Central reviewers
`prospectively reviewed efficacy data to provide an objective, unbiased inde-
`pendentreview ofclinical outcomes blinded to institution information, demo-
`graphic
`information, and investigator assessments. Central
`reviewers
`consisted offour experts in radiology and hematology/oncology. Tworadiol-
`ogistsfirst evaluated medical imaging datain a blinded independent radiology
`review, with adjudication by a third radiologist as needed, followed by an
`independent overall hematologist/oncologist review of radiology results in
`conjunction with pertinent clinical data to determine response, Central re-
`viewers provided the primary efficacyresults for this study.
`
`Statistical Analyses
`Primary efficacy end points were evaluated following six cycles (+ 1
`month) of lenalidomide or on treatment discontinuation. Patients discontin-
`uing before achieving a response or who switched to another therapy were
`considered nonresponders. Response rates were calculated with two-sided
`
`2
`
`JournaL oF CLinicaL ONCOLOGY
`© 2013 by American Society of Clinical Oncology
`Information downloaded from jco.ascopubs.org and provided by at Celgene on September 4, 2013 from 216.118.82.254
`Capyright © 2013 American Society of Clinical Oncology. All rights reserved.
`
`Apotex Ex. 1008, p. 12
`
`Apotex Ex. 1008, p. 12
`
`

`

`
`
`
`Lenalidomide in Relapsed/Refractory MCL Postbortezomib (MCL-001)
`
`
`
`Table 1. Patient Demographics, Baseline Disease Characteristics at Time of
`Study Entry, and Prior Antilymphoma Treatment (N = 134)
`No. of Characteristic
`
`Patients
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Age, years:
`= 65
`Male
`Stage Ill to IV
`ECOG PS
`0-1
`2
`Moderate-severe renal insufficiency*
`Time from original MCL diagnosis to
`enrollment. years
`<3
`23
`MIPI score group at enrollment
`Intermediate
`High:
`Positive bone marrow involvementt
`High tumor burdent
`Bulky disease§
`No. of prior treatment regimens
`No. of prior systemic antilymphoma
`therapies
`2
`3
`24
`Received prior bortezomib -
`Refractory to prior bortezomib
`Refractory to last therapy
`Received priar high-dase or dose-
`intensive therapy|
`
`Received prior bone marrow or
`
`autologous stem cell
`
`transplantation
`;
`
`Time from last prior systemic
`
`antilymphoma therapy, months
`
`<6
`96
`72
`
`
`26
`38
`28
`
`Abbr