1. Andre Goy, MD Chairman and Director John Theurer Cancer Center Lymphoma Program Head Professor of Medicine UMDNJ Mantle Cell Lymph oma “ Novel Therapies” 1 st International Educational Symposium on Mantle Cell Lymphoma

2. Disclosure Celgene, Millennium, Pharmacyclics: Research support (clinical trials).

3. 11/11/11 On 11.11.11, the time and date will be a perfect same-numbered palindrome - reading the same backwards as forwards - an event which can only happen on one day every 100 years….

4. 11/11/11 Doomsday...? More weddings... New spiritual Era ? Good luck??

5. Special Dates in the Maya Calendar …. "They were actually preparing for this catastrophe by buying real estate on high places and by stocking up on whatever the 16th-century equivalent of duct tape and bottled water was," John Hoopes, Maya History Scholar….

6. Our sponsors and organizing committee All my co-investigators and colleagues All patients and families All staff nurses and beyond…

7. The entire TEAM without whom we COULD NOT do what we DO!!!

10. MCL median OS has improved (from 2.5y to > 5y) over last 2 decades

12. MCL Remains a Challenge in the Relapse Setting FFS Poor outcome with conventional cytotoxics Med duration of response ≈ 6ms with “regular” chemo regimens 29 pts Classic R-HyperCVAD Wang, Cancer Nov 2008

13. Tam, Blood April 2009 MCL Remains a Challenge in the Relapse Setting HDT- ASCT much << in relapse setting Addition of rituximab beneficial only frontline setting

14. New Cytotoxics

15. New Cytotoxics: Bendamustine Leoni, Sem Hematol, April 2011 Strong alkylating agent Developed in Germany in the mid-twentieth century

16. New Cytotoxics: Bendamustine Ohamchi, Cancer Science Sept 2010 69 pts (11 MCL) Japan MCL: ORR 100% / 73% CR-CRu Bendamustine (120 mg/m(2) ) days 1-2 of a 21-day cycle x 6 cycles At a median follow up of 12.6 months, median PFS not reached

17. New Cytotoxics: Bendamustine Robinson, JCO Sept 2008 B + R in relapsed indolent B-cell NHL and MCL Rituximab: day 1: 375mg/m 2 + Bendamustine (90 mg/m(2) ) days 2&3 28-day cycle x 6 cycles Subtype No. of Patients ORR (%) CR (%) CRu (%) PR* (%) SD (%) PD (%) Total 66 92 41 14 38 8 0 Pathologic subtype Indolent NHL 54 93 41 13 39 7 0 MCL 12 92 42 17 33 8 0 Rituximab exposure Prior rituximab 37 87 35 14 38 14 0 No prior rituximab 29 100 48 14 38 0 0

18. STiL: First-line Bendamustine + Rituximab in Pts With FL, MCL, MZL Rummel MJ, et al. ASH 2009. Abstract 405. 90 MCL pts subset Bendamustine-Rituximab (n = 260) B 90 mg/m 2 day 1 and 2 R 375 mg/m 2 day 1 Max 6 cycles, q 4 weeks R-CHOP (n = 253) Max 6 cycles, q 3 weeks Stage III or IV CD20+ NHL (N = 549)

20. New Biologicals (also called targeted agents)

21. Targeting the Proteasome Ruschak A M et al. JNCI J Natl Cancer Inst 2011;103:1007-1017

22. Yewdell, Nat Immunl. Rev 3, 952-961 The Ubiquitin–proteasome Pathway Aaron Ciechanover Avram Hershko Irwin Rose Nobel Prize in Chemistry 2004

23. Through this pathway, the cell gets rid of excess / redundant proteins and misfolded / abnormal proteins and regulates biological processes (homeostasis).

26. Sites of action of proteasome inhibitors Ruschak A M et al. JNCI J Natl Cancer Inst 2011;103:1007-1017

27. Proteasome Inhibitors Chemical structure Name Type Developer Route of administration Devlpt. status Bortezomib Reversible Millennium: The Takeda Oncology Company IV FDA approved CEP-18770 Reversible Cephalon IV, oral Phase I MLN-9708 Reversible Millennium: The Takeda Oncology Company IV, oral Phase I Carfilzomib Irreversible Onyx IV Phase Ib ONX 0912 Irreversible Onyx Oral Phase I NPI-0052 Irreversible Nereus IV Phase I

28. Ruschak A M et al. JNCI J Natl Cancer Inst 2011;103:1007-1017 Effects of Proteasome Inhibition on Tumor and Stromal Targets Microenvironment ↓ NF-  B, ↓ cytokines, ↓ cell adhesion molecules, ↓ VEGF, ↓ TNF- α Apoptosis ↑ p53, ↑ p21, ↑ Bax, ↑ tBID, ↑ Bcl-2, ↓ MAPK, ↓ survivin, ↓ XIAP, ↓ cIAP ↑ Caspases Cell Cycle Arrest ↑ p53, ↑ p21, ↑ p27, ↓ NF-  B, ↓ MAPK, ↑ cyclins A/B/D/E, ↑ c-fos/c-jun, ↑ Myc, ↑ beta catenin Stress Response ↓ DNA repair, ↓ Pgp, ↑ TopII, ↑ TopI, ↓ NF-  B, ↓ MAPK, chemo- and radiosensitization Accumulation of abnormal mutated /or misfolded proteins

30. Bortezomib: 1 st in class approved in NHL – 1 st activity shown in mantle cell lymphoma

31. 1. O’Connor OA, et al. Br J Haematol. 2009;145:34-39. 2. Goy A, et al. J Clin Oncol. 2005;23:667-675. 3. Strauss SJ, et al. J Clin Oncol. 2006;13:2105-2112. 4. Belch A, et al. Ann Oncol. 2007;18:116-121. 5. Fisher RI, et al. J Clin Oncol. 2006;24:4867 -48 74. Similar ORR across studies and for untreated / relapsed 1.5 mg/m 2 1.3 mg/m 2 Bortezomib: Summary of Efficacy in Mantle Cell Lymphoma Study N CR PR ORR, % O’Connor [1] 40 5 (13) 14 (35) 47 Goy [2] 29 6 (20.5) 6 (20.5) 41 Strauss [3] 24 1 (4) 6 (25) 29 Belch, n [4] 13 untreated/ 15 relapsed 0 1 6 6 46 47 PINNACLE, n (%) [5] 141 11 (8) 36 (26) 47 (33) Total 262 24 (9) 74 (28) 98 (37)

32. Response / Subset Analysis Median DOR in pts with CR/CRu not reached at 26.5 mos Goy A, et al. Ann Oncol. 2009;20:520-525. Fisher RI, et al. J Clin Oncol. 2006;24:4867-4874. Bortezomib: PINNACLE Trial Update Parameter Response Evaluable (n = 141) Refractory MCL* (n = 58) Prior High- Intensity Therapy † (n = 58) ORR, % 32 29 25 CR/CRu, % 8 6 10 Median DOR, mos 9.2 5.9 Not reached

33. Most common adverse events (AEs, N=155) Fisher RI et al. J Clin Oncol . 2006;24:4867-4874 Gerecitano J et al. Br J Haematol . 2006;134(4):391-398 Frequent Supportive care Do not stop RX Predictive response? ORR 73% vs 33% w/o rash Toxicity Any grade n (%) Grade ≥ 3 n (%) Fatigue 95 (61) 19 (12) Peripheral neuropathies NEC 85 (55) 20 (13) Constipation 77 (50) 4 (3) Diarrhea NOS 73 (47) 11 (7) Nausea 68 (44) 4 (3) Rash NOS 43 (28) 4 (3) Vomiting NOS 42 (27) 4 (3) Anorexia 36 (23) 5 (3) Dizziness (excluding vertigo) 36 (23) 5 (3) Dyspnea NOS 35 (23) 7 (5) Insomnia 33 (21) 1 (< 1) Thrombocytopenia 33 (21) 17 (11)

36. Chang et al, BJH Aug 2011 CR, CRu, PR Rituximab 375 mg/m 2 d1 Cyclophosphamide 300 mg/m 2 q12h / d1-3 Doxorubicin 50 mg/m 2 48 h CI d1-2 Vincristine 2 mg d3 Dexamethasone 40 mg d1-4 6 cycles Rituximab 375 mg/m 2 qw × 4 q6mo × 4 Untreated MCL (N= 30) + Bortezomib 1.5mg / m 2 d 1 and 4 ONLY q 21d excessive neuropathy  changed to 1.3mg/m 2 and vincristine to 1mg Phase II study University of Wisconsin & Wisconsin Oncology Network – 30 pts ORR 90% CR rate 77% 3-year PFS 63% and OS 86% Modified R-HyperCVAD + Bortezomib

39. MCL – Other Bortezomib Combinations Combination Design Results / comments SWOG S0601 R-CHOP-Bz induction + 8 cycles maintenance Bz Phase II completed NCT 00376961 R-CHOP vs R-CHBzP Replacing vincristine with Bz Phase III ongoing NCT00722137

40. MCL – Other Bortezomib Combinations Combination Design Results / comments SWOG S0601 R-CHOP-Bz induction + 8 cycles maintenance Bz Phase II completed NCT 00376961 R-CHOP vs R-CHBzP Replacing vincristine with Bz Phase III ongoing NCT00722137 CALGB C50403 HDT/ASCT  Maintenance Bz vs Consolidaton Bz Randomized phase II maint vs consolidation

41. MCL – Other Bortezomib Combinations Combination Design Results / comments SWOG S0601 R-CHOP-Bz induction + 8 cycles maintenance Bz Phase II completed NCT 00376961 R-CHOP vs R-CHBzP Replacing vincristine with Bz Phase III ongoing NCT00722137 CALGB C50403 HDT/ASCT  Maintenance Bz vs Consolidaton Bz Randomized phase II maint vs consolidation NCI/Wilson Bz  R-EPOCH-Bz  Maintenance randomization Window of opportunity markers / circulating MCL cells

42. MCL – Other Bortezomib Combinations Combination Design Results / comments SWOG S0601 R-CHOP-Bz induction + 8 cycles maintenance Bz Phase II completed NCT 00376961 R-CHOP vs R-CHBzP Replacing vincristine with Bz Phase III ongoing NCT00722137 CALGB C50403 HDT/ASCT  Maintenance Bz vs Consolidaton Bz Randomized phase II maint vs consolidation NCI/Wilson (Grant ASCO 2011 #8022) Bz  R-EPOCH-Bz  Maintenance randomization Window of opportunity markers / circulating MCL cells Bendamustine + R + BTZ (Friedberg/ Blood March 2011) Relapsed / ref indolent NHL BR (benda 90mg.m 2 ) BTZ 1.3 days 1,4,8,11 29 pts 16FL, 7 MCL ORR 93% / 71% in MCL 2y PFS 47% CALGB BTZ + Len >10/19 pts resp / ongoing

43. O ’Connor. Clin Lymphoma Myeloma . 2005;6:191; Leonard. Int J Cancer . 2006;119:971; Demo. Cancer Res . 2007;67:6383; Ahn. Blood . 2007 Stewart. ASCO 2007 (abstr 8003); Chauhan. Br J Cance r. 2006;95:961. Other Proteasome Inhibitors Marizomib (NPI-0052) Phase I Bortezomib Approved for MCL Carfilzomib (PR-171) Phase II-III MM Highly selective for chymotrypsin-like Inhibits both chymotrypsin-like and caspase-like Binds all 3 enzymatic sites Reversible Irreversible Irreversible

44. O’Connor Clin Cancer Res Nov 2009 Stewart ASCO 2007 ORR 54% in BTZ-naive patients and 26% in pts w/ prior exposure to bortezomib Activity in WM / NHL phase II P / Tox: hematological, NO or minimal neuropathy Carfilzomib 0 % proteasome inhibition D2 D8 D9 D1 0 Time (weeks) D15 D16 D1 D5 1 2 3 4 D14 D28 80 80 1 2 PX-171-001 QDx5; 9 day rest 2 week cycle Continuous suppression of proteasome activity PX-171-002 QDx2 weekly for 3 wks; 12 day rest 4 week cycle Prevent full recovery of proteasome between doses

45. Annual “Celebrating Life and Liberty” Cancer Survivors Event JTCC - Sept 2011

46. Lenalidomide mechanisms of action remains poorly understood / pleiotropic effects Antiangiogenic, microenvt, direct antiproliferative, NK, and T-regs List A. N Engl J Med. 2007;357:2183-2186. Ramsay AG, et al. J Clin Invest. 2008;118: 2427-2437. Lenalidomide / IMiDs Lenalidomide repairs suppressed T-cell immunological synapse formation in CLL and follicular lymphoma

48. NHL-003: MCL subset 54 pts Zinzani et al. ASH # 262 Reeder ASCO 2009, abst # 8569 Patients (%) PFS (days) Kaplan-Meier Estimates (n=54) Response Duration (days) Kaplan-Meier Estimates (n=23) Median Response Duration has not been reached Responders (%) Lenalidomide in MCL – Trial 003 100 80 40 20 0 60 0 100 200 300 400 100 80 40 20 0 60 0 100 200 300 400

49. Zaja Ash 2010, abst # 966 Ahmadi ASH 2010, abst # 3962 Lenalidomide in MCL – Next Step Study Results/Comments MCL-001 “EMERGE” Rel / ref MCL: single agent 25 mg/pivotal trial 117 / 135 pts enrolled MCL-002 “SPRINT” Randomized rel / ref MCL: lenalidomide vs invest’s choice

50. Wang ICML 2011 Morrison, ASCO 2010 abst # 8106 Lenalidomide in MCL – Next Step Study Results/Comments Len + Rituximab Len 20mg 21/28 days + R 375 mg /m 2 x 4 46 pts (1-4 prior RX) / ORR 57% 33% CR Median duration of response 18.9 ms Gr 3-4 toxicities: neutropenia (17%), lymphopenia (7.2%), and thrombocytopenia (4.5%) Len + Bortezomib CALGB / ongoing / target 54 pts Len + Bortezomib + Rituximab Sarah Cannon / ongoing

51. Targeting PI3K/mTOR Pathway PI3K/mTOR pathway functions like an “integrator” of cell stimuli from the environment (cell surface through number of receptor kinases) and available “nutrients” to allow cell survival / proliferation PI3K and mTOR signaling critically regulates metabolism, growth or survival Witzig T et al, Current Treat Oncol, July 2006

53. Temsirolimus – Phase III MCL Multicenter, open-label, phase III trial, International study 54 patients per arm; 2 -7 previous therapies Temsirolimus treatment to continue until progression or unacceptable toxicity Hess, JCO, Aug 2009 Temsirolimus 175 mg qw x 3 then 25 mg qw R A N D O M I Z E Relapsed/refractory MCL Required rituximab anthracycline alkylating agent (N = 162) Investigators’ choice single agent Temsirolimus 175 mg qw x 3 then 75 mg qw

54. Temsirolimus – Phase III MCL Multicenter, open-label, phase III trial Hess, JCO, Aug 2009 Most common grade 3 or 4 AEs in the temsirolimus groups were thrombocytopenia, anemia, neutropenia and asthenia Approved in EU

55. Witzig T et al, J Clin Oncol 2005;23:5347-5356 Rizzieri DA et al, Clin Can Res 2008;14:2756-2762 Yee KW et al, Clin Cancer Res 2006;12:5165-5173 Reeder CB et al, ASH 2007, abstr 121 Hesse G et al, ASCO 2008, abstr 8513 mTOR Inhibitors – Next Step Drugior BTZ) Design Results/Comments Temsirolimus (CCI-779) Temsirolimus + rituximab Relapsed MCL / > CR Rituximab, Cladribine, and Temsirolimus Other comb w/ R-CHOP/ BBR etc..

56. Witzig T et al, J Clin Oncol 2005;23:5347-5356 Rizzieri DA et al, Clin Can Res 2008;14:2756-2762 Yee KW et al, Clin Cancer Res 2006;12:5165-5173 Reeder CB et al, ASH 2007, abstr 121 Hesse G et al, ASCO 2008, abstr 8513 mTOR Inhibitors – Next Step Drugior BTZ) Design Results/Comments Temsirolimus (CCI-779) Temsirolimus + rituximab Relapsed MCL / > CR Rituximab, Cladribine, and Temsirolimus Other comb w/ R-CHOP/ BBR etc.. Everolimus (RAD001) Oral 10 mg QD until PD or toxicity MCL 19 cases ORR: 32%; 11% CR, DOR 5.5 ms Well tolerated: Gr 3-4 neutropenia 17% thrombocytopenia 35% Same design for phase II pivotal trial (PILLAR-1) (prior BTZ) International study completed

57. Witzig T et al, J Clin Oncol 2005;23:5347-5356 Rizzieri DA et al, Clin Can Res 2008;14:2756-2762 Yee KW et al, Clin Cancer Res 2006;12:5165-5173 Reeder CB et al, ASH 2007, abstr 121 Hesse G et al, ASCO 2008, abstr 8513 mTOR Inhibitors – Next Step Drugior BTZ) Design Results/Comments Temsirolimus (CCI-779) Temsirolimus + rituximab Relapsed MCL / > CR Rituximab, Cladribine, and Temsirolimus Other comb w/ R-CHOP/ BBR etc.. Everolimus (RAD001) Oral 10 mg QD until PD or toxicity MCL 19 cases ORR: 32%; 11% CR, DOR 5.5 ms Well tolerated: Gr 3-4 neutropenia 17% thrombocytopenia 35% Same design for phase II pivotal trial (PILLAR-1) (prior BTZ) International study completed Next generation mTORi CC223 OSI-027 ( TORC1 and TORC2 inhibition) / ongoing

58. CXCR5 BAFFR Stromal cell IL-6R CXCL13 BAFF IL-6 PI3K Inhibitors PI3K Delta Pathway Drives Proliferation Cell survival Trafficking BCR PI3K Delta CD40 STAT T308 S473 AKT JAK TRAF6 NF-  B pathway JAK mTOR BTK PLC  2 PKC GSK-3 LYN SYK    LYN/SYK T-cell Signaling stimulus gp130 gp130 STAT BTK PLC  2 p70s6k elf4E Malignant B-cell membrane

59. CAL-101 Selectivity relative to Class I PI3K isoforms involved in insulin signaling and other physiological functions No off-target activity against Class II or III PI3K, mTOR, or DNA-PK No off-target activity seen in screen of >350 protein kinases (Ambit KINOMEscan™) Reference: Lannutti, Blood 2010 CAL-101 is an Orally Bioavailable Small Molecule that Inhibits PI3K Delta Class I PI3K Isoform Cell-Based Activity PDGF-induced pAKT LPA-induced pAKT fMLP-induced CD63+ Fc  R1-induced CD63+ EC 50 (nM) >20,000 1,900 3,000 8 Alpha Beta Gamma Delta

60. Single-Agent CAL-101 in NHL and CLL NHL (N=51) Characteristic MCL (N=21) iNHL (N=30) CLL (N=54) Age, median [range], years 71 [52-82] 61.5 [32-85] 62.5 [37-82] Bulky disease, % 57 50 81 Adverse genetics (del 17p), % -- -- 36 Prior therapies, median [range], n 5 [1-12] 4 [1-10] 5 [2-15] Prior therapy type, % Rituximab 100 100 98 Alkylating agent 100 87 87 Anthracycline/anthracenedione 95 50 -- Purine analog -- 30 100 Bortezomib (MCL)/Alemtuzumab (CLL) 76 -- 31

62. MCL (n=21) iNHL (n=30) CLL (n=54) Variety of dosings from 50 BID to 350 BID Kahl, ASH 2010, abst # 17777 O’Brien, Pan Pacific NHL Conf, Aug 2011 Single-Agent CAL-101 in NHL and CLL

64. Chen, Blood 2008 Irish J M et al. PNAS 2010;107:12747-12754 Targeting the BCR Pathway in Lymphoma

68. Fowler, Blood ASH 2010; 116 : 964. Advani,ICML, Lugano 2011 Phase I NHL / CLL – Enrollment (56 pts) Median age, years (range) M/ F, n (%) 65 (41-82) 38 (68) / 18 (32) Histology, n (%) FL 16 (29) CLL/SLL 16 (29) MCL 9 (16) DLBCL 7 (16) MZL / MALT 4 (7) WM 4 (7) Median prior therapies, number (range) 3 (1-10)

69. 1 AEs >14% * Ecchymosis and pneumonia are combination of several preferred terms Grade 3/4 Hematology 2 Most Common Adverse Events 1 2 Based on clinical review of AE and Lab data Fowler, Blood ASH 2010; 116 : 964. Advani, ICML, Lugano 2011 Phase I NHL / CLL - Adverse Events

70. Pre-treatment 2 months on treatment Absolute Lymphocyte Count O’Brien, Pan Pacific NHL Conf, Aug 2011 Burger, O‘Brien, ASH 2010, Blood 116: abst # 57 Pattern of Response: Blood Lymphocytes vs Lymph Nodes

71. 2 Based on clinical review of AE and Lab data * 1 CLL pt had nodal response with lymphocytosis; ** Based on IgM Fowler, Blood ASH 2010; 116 : 964. Advani,ICML, Lugano 2011 Phase I – PCI-32765 – Best Response N CR PR SD PD NE ORR% ITT (n=56) ORR% Eval (n=50) CLL/SLL 16 1 10 3 * 2 69% 79% MCL 9 3 4 1 1 78% 78% WM 4 3 ** 1 75% 75% FL 16 3 3 3 4 3 38% 46% MZL/MALT 4 1 1 1 1 25% 33% DLBCL 7 2 1 4 29% 29% TOTAL 56 7 24 9 10 6 55% 62%

72. % Change of Tumor Burden 41/48 (85%) Fowler, Blood ASH 2010; 116 : 964. Advani,ICML, Lugano 2011 PCI-32765 Max % Change in Tumor Burden CLL/SLL MCL DLBCL FL Other Indolent NHL

74. Other Targets in MCL Parek, Semin Cancer Biol. 2011

76. Induction Consolidation Maintenance Relapse MCL: Considerable Progress! CHOP/ CVP/ MCP / Fludarabine BEFORE ASCT Debated?? No maintenance IFN ? HDT / ASCT Dose-intensive Therapies HD AraC and Rituximab NOW HDT / ASCT Rituximab Bortezomib? BTZ, CFZ New Mab Lenalidomide mTORi BTKi PI3Ki Other: Bcl-2, HADCi

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