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Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma ASH Review 2012 Stephen Spurgeon

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1 Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma ASH Review 2012 Stephen Spurgeon

2 Disclosures Speakers Bureau: GSK, Millenium, Cephalon

3 CLL: Pertinent Topics ● ASH treatment updates ● James DF, et al. ASH Abstract 291. ● Foa R, et al. ASH Abstract 294. ● Badoux XC, et al. ASH Abstract 980. ● FCR treatment expectations ● Fink A, et al. ASH Abstract 977. ● Rational therapeutic targets and novel agents

4 Rituximab + Lenalidomide for Patients With Previously Untreated CLL: Phase II ● Patients with previously untreated CLL (n = 69) – Patients younger than 65 yrs of age: n = 40 – Patients 65 yrs of age or older: n = 29 ● Primary endpoint: CR in patients 65 yrs ● Secondary endpoints – Safety, ORR, PFS James DF, et al. ASH Abstract 291.

5 Rituximab + Lenalidomide in Previously Untreated CLL: Study Design ● Treatment protocol: 7 cycles – Cycle 1: lenalidomide on 21 of 35 days – Cycles 2-7: lenalidomide on 21 of 28 days James DF, et al. ASH Abstract 291.  Rituximab – 50 mg/m 2 on Day 29 of C 1 – 325 mg/m 2 on Day 31 of C 1 – 375 mg/m 2 on Day 33 of C 1 – 375 mg/m 2 /wk x 4 for cycle 2 – 375 mg/m 2 on Day 1 of C 3-7  Lenalidomide – Day 1: Starting dose: 2.5 mg/day – Day 8: Escalated to 5 mg/day – Day 1 cycle 3: increase to 10 mg/day  Tumor lysis syndrome prophylaxis with allopurinol 300 mg/day and oral hydration  Thromboprophylaxis (aspirin 81 mg/day) added after 2 cases of pulmonary embolism  Methylprednisolone for tumor flare reaction and growth factor support as needed

6 Rituximab + Lenalidomide for Patients With Previously Untreated CLL: Efficacy ● ORR associated with higher median lenalidomide dose in younger patients (P =.05) ● Greater exposure to lenalidomide in younger patients vs older patients James DF, et al. ASH Abstract 291. Outcome Younger Than 65 Yrs (n = 40) 65 Yrs or Older (n = 29) ORR, %  CR  CRi  Nodular PR  PR PD04 Median PFS, mos  Median follow-up

7 Rituximab + Lenalidomide for Patients With Previously Untreated CLL: Toxicity James DF, et al. ASH Abstract 291. AEs, % Younger Than 65 Yrs (n = 40) 65 Yrs or Older (n = 29) Any toxicity  Grade 1/2  Grade 3/ Nonhematologic toxicity  Grade 1/2  Grade 3/ Tumor flare reaction  No  Yes 18 83* *P =.05 vs older patients.

8 ML21445: Rituximab + Chlorambucil Induction Therapy in Elderly Patients ● Patients with previously untreated CLL (N = 97) – Ineligible for first-line R-FC ● 8 cycles (q 28 days) ● Primary endpoint: ORR at end of induction Foa R, et al. ASH Abstract 294. Chlorambucil 8 mg/m 2 /day Days 1-7 Rituximab 375 mg/m 2 Day 1 of cycle mg/m 2 on Day 1 > C4 PR, CR observation R 375 mg/m 2 8 wks for 12 doses

9 ML21445: Responses *By flow cytometry. Foa R, et al. ASH Abstract 294. Response Following Induction, % Patients (ITT) (N = 85) ORR  All patients 81.2  Binet stage A 86.0  Binet stage B 80.0  Binet stage C 79.0  yrs of age 84.0  yrs of age 85.0  yrs of age or older 75.0  75 yrs of age 81.0 Response Following Induction, % Patients (ITT) (N = 85) CR/CRi19 PR60.0 PD3.5

10 ML21445: Efficacy ● No correlation between treatment response and standard prognostic factors ● Pretreatment gene expression differed between responders and nonresponders – Up-regulation of transcripts relevant to pro-proliferative and antiapoptotic pathways, including Ras (K-Ras, N-Ras) and Rho – Up-regulation of genes related to protein metabolism – CD20 down-regulation detected by gene profiling (P =.018 vs responders) but not by flow cytometry (P =.19 vs responders) Foa R, et al. ASH Abstract 294.

11 ML21445: Toxicity ● Chlorambucil dose reduction required in 7.8 % of cycles ● Grade 3/4 Hematologic AEs during induction: – Neutropenia: 19.6% – Thrombocytopenia: (1.0%) – Infections: (1.0%) ● Grade 3/4 neutropenia during maintenance: – 11.8% with rituximab vs 3.1% on observation Foa R, et al. ASH Abstract 294.

12 Identifying High Risk for Progression in CLL Patients Receiving FCR ● CLL8 study: FC vs FCR as primary CLL therapy [1] – Median PFS: 57.9 mos FCR vs 32.9 mos FC (P <.0001) – OS dependent on length (< vs ≥ 2 yrs) of PFS (P <.001) – shortened PFS: ● del(17p) + TP53 mutations ● MRD, [2] IgVH unmutated status, [3] shorter PFS – Elevated β 2 -microglobulin or high WBC count not predictive of short PFS 1.. Hallek M, et al. Lancet. 2010;376: Boettcher S, et al. ASH Abstract Stilgenbauer S, et al. ASH Abstract 781.

13 Identifying High Risk for Progression in CLL Patients on FCR: Study Design ● Subset analysis of GCLL CLL8 [1] randomized phase III trial (FC vs. FCR) – FCR-treated patients from CLL8 with short PFS and MRD at final restaging (N = 143) ● Definition of high risk for early progression – MRD levels > or – MRD levels > to < plus either ● del(17p), TP53 mutation, or IgVH unmutated status Fink A, et al. ASH Abstract Hallek M, et al. Lancet. 2010;376:

14 Identifying High Risk for Progression in CLL Patients Receiving FCR: PFS and OS ● Survival outcomes significantly better in patients with CLL and low risk – Median PFS in low-risk vs high-risk patients ● 69 vs 22 months ● HR: 6.4 (95% CI: ; P <.0001) – Median OS in low-risk vs high-risk patients ● Not reached vs 57 mos ● HR: (95% CI: ; P <.0001) Fink A, et al. ASH Abstract 977.

15 Lenalidomide + Rituximab Combination in Relapsed/Refractory CLL: Efficacy Badoux XC, et al. ASH Abstract 980. OutcomePatients (N = 59) Clinical best response, %  ORR 66  CR* 12  Nodular PR 12  PR mo OS, % (95% CI)75 (64-87) Median PFS, mos (95% CI)17.4 ( ) *Minimal residual disease-negative CR.

16 Lenalidomide + Rituximab Combination Therapy in Relapsed/Refractory CLL ● Patients with relapsed/refractory CLL (N = 59) ● Treatment protocol: 28-day cycles – Rituximab 375 mg/m 2 ● Cycle 1: Days 1, 8, 15, 22 ● Cycle 2: no administration ● Cycles 3-12: Day 1 – Lenalidomide 10 mg/day starting Day 9 – Allopurinol 300 mg orally Days 1-14 for tumor lysis prophylaxis ● Primary endpoint: ORR – ITT analysis – Assessed at end of cycles 3, 6, then Q 6 months Badoux XC, et al. ASH Abstract 980.

17 Lenalidomide + Rituximab Combination in Relapsed/Refractory CLL: Efficacy  Lenalidomide/rituximab responses not correlated with disease biology ● Rai stage, bulky disease, cytogenetics by FISH: correlation insignificant – Fludarabine refractory patients do worse ● Lower ORR (P <.05) ● Shorter PFS (P =.019) Badoux XC, et al. ASH Abstract 980.

18 Lenalidomide + Rituximab Combination in Relapsed/Refractory CLL: Toxicity Badoux XC, et al. ASH Abstract 980. Grade 3/4 AEs, n (%)Patients (N = 59) Neutropenia43 (73) Thrombocytopenia20 (35) Anemia9 (15) Any infection14 (24)  Pneumonia/bronchitis 6 (10) Febrile neutropenia6 (10) Hypercalcemia*1 (2) Gastrointestinal3 (5) Tumor lysis1 (2) VTE1 (2) Pain1 (2) Weakness1 (2) Arrhythmia1 (2) ● Frequent grade 1/2 AEs – Fatigue (37%) – Diarrhea (36%) – Tumor flare (27%) – Sensory neuropathy (24%) – Rash (22%) ● 4 patients experienced secondary malignancies on treatment – Myelodysplastic syndrome: n = 1 – Squamous cell carcinoma: n = 1 – Melanoma in situ: n = 1 – Head/neck cancer recurrence: n = 1

19 Summary ● Rituximab + lenalidomide active, well tolerated in both younger and older patients (younger than 65 or 65 yrs or older) with previously untreated CLL but produced higher ORR and CR in the younger cohort ● Rituximab + chlorambucil induction therapy active, well tolerated in elderly patients with previously untreated CLL ● In patients with CLL receiving FCR, cytogenetic analysis plus MRD detection identifies patients at high risk of disease progression ● Lenalidomide + rituximab combination is active as salvage therapy for patients with relapsed/refractory CLL and has a manageable AE profile; response rates were lower among patients with fludarabine-refractory disease

20 CLL is a Complex Disease Diagram courtesy of Jan Burger

21 Therapeutic targeting of the BCR Signaling Pathway Stevenson et al. Blood

22 Rationale for Targeting PI3K-δ in CLL PI3-kinase active in CLL vs normal B-cells PI3K-δ inhibition in CLL cells promotes ↑ Apoptosis ↓ Proliferation ↓ Chemokines ↓ Microenvironment response Herman S et al: Blood 2010 Lanutti B, et al: Blood 2011

23 CharacteristicsN=55 Sex, males/females, %82/18 Age, median[range], years63 [37-82] Bulky adenopathy (  5 cm), % 82 Adverse genetics, % del(17p)31 Relapsed/refractory disease, %29/71 Prior therapies, median [range], n5 [2-15] Prior therapy type, % Fludarabine100 Rituximab98 Alkylating agent87 Alemtuzumab33 Phase I Cal-101 (GS-1101) Patient Demographics

24 CAL-101 (GS-1101) Response in CLL Coutre S, et al: ASCO 2011

25 Patient B.C. Diagnosed with CLL in year old man with relapsed bulky CLL Since 2005: 8 treatment regimens 2010 progressive disease

26 Refractory CLL-pre treatment Refractory CLL-after 1 cycle of CAL-101

27 GS-1101 Progression Free Survival Coutre S, et al: ASCO 2011

28 GS-1101 Grade 3-4 Toxicity Coutre S, et al: ASCO 2011

29 Where is GS-1101 Going in CLL? ● Completion of phase I or II studies in untreated and relapsed CLL – GS combinations (Sharman et al. Abstract # 1787) ● Registration studies in CLL ● OHSU expects to have: – GS1101 (CAL-101) registration trial for relapsed CLL – Novel combinations with other kinase inhibitors

30 The Bruton’s Tyrosine Kinase (BTK) Inhibitor PCI Induces Durable Responses in Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Follow-up of a Phase Ib/II Study (abstract # 983) S USAN O'B RIEN, MD 1, J AN A. B URGER, MD, P H D 1, K RISTIE A. B LUM, MD 2, R ICHARD R. F URMAN, MD 3, S TEVEN E. C OUTRE, MD 4, J EFF S HARMAN, MD 5, I AN W. F LINN, MD, P H D 6, B ARBARA G RANT, MD 7, N YLA A. H EEREMA, P H D 2, A MY J. J OHNSON, P H D 2, T ASHEDA N AVARRO 8, E RIC H OLMGREN, P H D 8, E RIC H EDRICK, MD 8 AND J OHN C. B YRD, MD 2 1 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 2 Division of Hematology and The Department of Pathology, The Ohio State University, Columbus, OH 3 Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY 4 Divisions of Hematology and Oncology and Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA 5 US Oncology, Springfield, OR 6 Sarah Cannon Research Institute, Nashville, TN 7 Medicine, Vermont Cancer Center, University of Vermont, Burlington, VT 8 Pharmacyclics, Inc, Sunnyvale, CA

31 31 PCYC-1102-CA Total enrollment 117 patients Relapsed/Refractory 420 mg/d (n=27) Dates enrolled: 5/20/10–9/27/10 Treatment Naïve ≥ 65 yrs 420 mg/d (n=26) Dates enrolled: 6/2/10–4/5/11 Relapsed/Refractory 840 mg/d (n=34) Dates enrolled: 10/9/10–4/5/11 High-risk Relapsed/Refractory 420 mg/d (n=25) Dates enrolled: 6/9/11–7/27/11 Treatment Naïve ≥ 65 yrs 840 mg/d (n=5) Dates enrolled: 5/31/11–7/8/11

32 Patient Characteristics (cont.) 420 mg/d (N=27)840 mg/d (N=34)Total (N=61) Cytopenia at baseline, # (%) ANC < 1500/μL HGB < 11g/dL Platelets < 100,000/μL HGB < 11g/dL or PLT < 100,00 μL 6/26 (23) 4 (15) 8 (30) 9 (33) 17 (50) 18 (53) 24 (71) 27 (79) 23/60 (38) 22 (36) 32 (52) 36 (59) Prognostic Markers, # (% ) IgVH unmutated: Del(17p): Del(11q): β2 Microglobulin > 3mg/L 17/25 (68) 9 (33) 8 (30) 9/25 (36) 18/31 (58) 10 (29) 12 (35) 20/32 (63) 35/56 (63) 19 (31) 20 (33) 29/57 (51) ECOG Performance Status, # (%) 0 1/2 11 (41) 16 (59) 13/33 (39) 20/33 (61) 24/60 (40) 36/60 (60) Refractory, # (%) 10 (37)17 (50)27 (44) Bulky Disease, # (% ) ≥ 5 cm ≥ 10 cm 13 (48) 1 (4) 20 (59) 9 (26) 33 (54) 10 (16) 32

33 420 mg/d (N=27) 840 mg/d (N=34) Total (N=61) CR1 (4)0 (0)1 (2) PR17 (63)23 (68)40 (66) ORR*67%68%67% Nodal6 (22)8 (24)14 (23) SD1 (4)1 (3)2 (3) PD1 (4)0 (0)1 (2) NE1 (4)2 (6)3 (5) Best Response *Per IWCLL 2008 criteria

34 Splenomegaly before and after 2 months of PCI Before PCI months of PCI-32765

35 Pattern of Response: Blood Lymphocytes vs Lymph Nodes

36 Best Response by Risk Features n/NORR % All Patients41/6068 Hgb < 11 g/dL or PLT < 100K/μL at screening35/6058 Del 17p12/1867 Del 11q14/2070 IgVH unmutated26/3574 β2 Microglobulin > 3mg/L19/2966 ≥ 70 years age13/1872 Refractory disease17/2665 Bulky disease ≥ 5 cm24/3373 Bulky disease ≥ 10 cm7/1070

37 Progression-free Survival by 17p Del Status

38 Common AEs (All Grades) Events occurring in > 15% of Patients (n=61) Grade 1 Grade 2 Grade 3 Grade 4

39 Grade 3/4 Infectious and Hematologic Toxicity Grade 3/4 Hematology toxicity mg/d (n=27) 840 mg/d (n=34) Neutropenia Anemia Thrombocytopenia Grade 3 Grade 4 4% 7% 0% 0% 7% Grade 3 Grade 4 12% 9% 9% 3% 9% 0% 1 Reported as AEs Grade 3/4 Infectious toxicity 420 mg/d (n=27) 840 mg/d (n=34) Patients with any Grade 3/4 (%, %) 5/2 (19%, 7%)9/1 (26%, 3%)

40 Dasatinib in CLL ● Inhibits SRC, LYN, BTK ● Results published on 15 relpased/refractory patients ● ORR 20% ● Nodal response 66% ● Can we do better? Amrein et al. Clinical Cancer Research 2011

41 ● Dasatinib Clinical Trial (NCT ) – Relapsed/refractory of if age > 70, Tx naive – Test patient CLL samples in the lab – Only enroll patients on trial if the drug first demonstrates in vitro killing activity – Measure cell death signaling pathways – Examine signaling and gene expression in vivo while receiving treatment Dasatinib in CLL at OHSU Can we predict who will respond to treatment?

42 C-F: Response to treatment C-F pretreatment scanC-F after 6 months of dasatinib

43 CF Response to treatment Lymphocyte Count 93 % change from baseline

44 Summary: Targeting BCR signaling in CLL ● Promising activity including in poor risk patients ● Most effective for nodal disease ● Often results in lymphocytosis as CLL cells are mobilized from the micro-environement ● Well tolerated, oral agents ● Studies to predict response and with novel combinations are ongoing

45 Mantle Cell Lymphoma ● Role of Rituximab – Kluin-Nelemans, et al. ASH Abstract 439 ● R-Cladribine Based Treatment – Spurgeon, et al. ASH Abstract 441 ● PCI in Mantle Cell Lymphoma – Wang, et al. ASH Abstract 442

46 MCL: Poor Prognosis and Long–Term Outcome Lenz G. et al. J Clin Oncol. 2005;23: Patients at risk R-CHOP CHOP Progression-free survival after CHOP and R-CHOP There were no significant differences between the two treatment arms (P=0.31) 18 months

47 Possible Improved Survival in Elderly Patients Receiving Rituximab Griffiths, R, et. al. Blood 2011 Nov 3;118(18): Percentage Surviving

48 R-Maintenance ● SAKK [1] –  NO BENEFIT after R induction ● GLSG [2] –  PFS BENEFIT after R-FCM induction ● Modified R-HyperCVAD [3] – 2 years of R-Maintenance – PFS = 37 months – Median OS = 70 months 1. Ghielmini M, et al. J Clin Oncol. 2005, 2. Forstpointner, R, et al. Blood 2006), 3. (Kenkre, V, et al. Leuk Lymphoma 2011)

49 R-CHOP vs R-FC followed by maintenance with Rituximab vs. Interferon-alfa in elderly patients with Mantle cell lymphoma Hanneke C. Kluin-Nelemans for the European MCL Network University Medical Center Groningen The Netherlands

50 8 x R-CHOP IFN-  maintenance (3 x 3 M IU/week) or Peg-IFN (1mg/kg week) PR, CR 6 x R-FC Rituximab maintenance (all 2 months) First RCT for MCL Elderly 8 countries, n = 560 (Jan 2004-Oct 2010) Newly diagnosed, >60-65 yr; performance 0-2, Stages II-IV, central PA review

51 MCL Elderly: Baseline Characteristics 1st randomization ParameterR-CHOP (%)R-FC (%) Age median (range) 70 (61-87)70 (60-85) % male 6872 Stage IV 8381 % pos. BM 7675 B-Symptoms 38 Performance Elevated LDH 4443 MIPI low risk 79 MIPI intermediate risk 4339 MIPI high risk 5052 n 280

52 MCL Elderly: Overall survival R-FC R-CHOP

53 MCL elderly study toxicity R-CHOP vs R-FC

54 MCL Elderly study Remission duration maintenance Intention-to-treat analysis IFN Rituximab

55 R-CHOPR-FC p=0.18 for interaction of induction and maintenance MCL Elderly study Remission duration related to induction

56 After R-CHOPAfter R-FC p= for interaction of induction and maintenance MCL Elderly: overall survival related to induction regimen

57 Toxicity of IFN and Rituximab

58 R-cladribine based Therapies for MCL Median PFS 37.5 months Median OS 85 months Spurgeon et. al, Leukemia & Lymphoma, 2011

59 R-cladribine based Therapies for MCL Spurgeon et. al, Leukemia & Lymphoma, 2011

60 Phase I/II Study of Vorinostat (SAHA), Cladribine (2-CdA), and Rituximab Shows Significant Activity in Previously Untreated Mantle Cell Lymphoma Stephen E. Spurgeon,MD 1, David F. Claxton, MD 2, W. Christopher Ehmann, MD 2, Samir S. Parekh, MD, 3 Violetta Leshchenko, PhD 3, Motomi Mori, PhD 2, Sara Shimko, BA, 2 August Stewart, BA, 2 Elliot M. Epner, MD PhD 2 1.Knight Cancer Institute at Oregon Health & Science University, Portland, OR 2.Penn State Hershey Cancer Institute, Hershey, PA 3.Albert Einstein College of Medicine, Bronx, NY

61 ● Cladribine has cytotoxic and epigenetic properties ● Vorinostat (SAHA): – inhibits class I and II histone de-acetylases (HDAC) – has shown clinical activity in B-cell lymphomas 1 – increases tumor suppressor gene expression when combined with a hypomethylating agent 2-4 ● Cladribine and HDAC inhibition are synergistic as evidenced by increased in vitro apoptosis in primary CLL cells. 5 Study Rationale 1.Human Pathology 2007;38(12): J Clin Oncol Mar 20;29(9): Cancer Sci (1): Blood Aug 19;116(7): Br J Haematol Jan;144(1):41-52.

62 Inclusion Criteria ● Treatment Population – Phase I: relapsed CD20+ NHL, CLL – Phase II: Two cohorts ● Relapsed CD20+ NHL, CLL ● Previously untreated MCL

63 Primary Study Objectives Phase I ● Safety and toxicity Phase II ● Response rates ● Tolerability and toxicity

64 Secondary Objectives ● Progression free survival ● Overall survival ● DNA methylation, histone deacetylation, and changes in target gene expression

65 Phase II dosing ● Phase I – No MTD reached – Responses were seen in MCL and SLL ● Phase II vorinostat dose 400 mg/day, days 1-14 cycle > 1 Rituximab once per cycle

66 Phase II: Response in Relapsed Cohort (n =17) PopulationTotalITT Overall Response (%) MCL 10 2 (20%) 2 CR MZL3 2 (66%) 1 CR, 1 PR FL1 1 PR (100%) Relapsed CLL30 NHL Response by Modified Cheson Criteria CLL Response by IWCLL Criteria

67 Phase II: Previously Untreated Mantle Cell Cohort ( n=21) Median Age (range) 64 ( 42-87) CharacteristicNumber of Patients (%) Age > 60 Stage IV Blastic Histology MIPI* low intermediate high B2 M > 3.0 g/dl 14 (70%) 20 (95%) 4 (19%) 11 (52%) 4 (19%) 6 (29%) 11 (52%) * Mantle Cell International Prognostic Index

68 Phase II: Clinical Response in Previously Untreated MCL Cohort (n =20) Response (%)Complete Remission (%) Partial Remission (%) 20 (100%)15 (75%)5 ( 25%)

69 EventFrequency (158 treatment cycles) Hematologic Neutropenia Thrombocytopenia Anemia Gr. 3 Gr (32%) 17 (11%) 32 (20%) 8 (5%) 8 (5%) 0 Non Hematologic Fatigue Infection Grade 5 Pulmonary Hemorrhage 6 (4%) 0 3 (2%) 0 1 (1%) Phase II Toxicity: Most Prevalent Adverse Events

70 Study currently enrolling patients at OHSU

71

72

73 Months * Off study

74 Summary: Mantle Cell Lymphoma ● Induction therapy with R-CHOP vs R-FC favors R-CHOP: more overall responses, less toxicity ● Rituximab maintenance doubles the remission duration in patients responding upon initial therapy Vorinostat, cladribine, and rituximab is safe and effective regimen for lymphoid malignancies All previously untreated MCL patients responded 75% CR PCI active and well tolerated in relapsed MCL

75 Reference/Backup Slides

76 Tumor Microenvironment ● CLL cells – Migrate to stromal cell layer which is protective – Secrete CCL3 and CCL4 which attracts T cells ● Lymph Nodes – CD40L engaged with CD40 on T-cells ● More sensitive to chemotherapy if removed from protective niche

77 Nurse-like cells ● Marrow stromal cells and nurse like cells – Secrete CXCL 12 and CXCL 13 – Attract CLL cells (via chemokine receptors CXCR4 and CXCR5) * Nishio M et al. Blood 106: , 2005 ¶ Burkle A et al. Blood 110: , 2007 † Burger JA et al. Blood 96, , 2000 ‡ Deaglio S et al. Blood 105(8): , 2005

78 ● Distinct differences between node and peripheral blood ● Increased expression of CCL3 and CCL4 in lymph nodes ● Increased expression of MYC Y Herishanu et al., Blood Jan 13;117(2): JA Burger et al. Blood. 113(13):3050-8, 2009

79 CCL3 and CCL4 levels affect prognosis Sivina M et al, Blood 117:1662-9, 2011

80 A Phase 1 Study of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3K  ) Inhibitor, GS-1101 (CAL-101), in Combination with Rituximab and/or Bendamustine in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) Reference: Sharman, ASH 2011, #1787 Jeff Sharman1, Sven de Vos2, John P. Leonard3, Richard R. Furman3, Steven E. Coutre4, Ian W. Flinn5, Marshall T. Schreeder6, Jacqueline Barrientos7, Nina D. Wagner-Johnston8, Thomas E. Boyd9, Nathan Fowler10, Leanne M. Holes11, Harriet (Sissy) Peterman11, Brian J. Lannutti11, Dave M. Johnson11, Thomas M. Jahn11, Langdon L. Miller11 1US Oncology Research and Willamette Valley Cancer Institute and Research Center, Springfield, OR; 2University of California Los Angeles, Los Angeles, CA; 3Weill Cornell Medical College, New York, NY; 4Stanford University Cancer Center, Stanford, CA; 5Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN; 6Clearview Cancer Institute, Huntsville, AL; 7Long Island Jewish Medical Center, New Hyde Park, NY; 8Washington University, St. Louis, MO; 9US Oncology Research and Yakima Valley Memorial Hospital, Yakima, WA; 10University of Texas, MD Anderson Cancer and Research Center, Houston, TX; 11Gilead Sciences, Inc., Seattle, WA

81 In Previously Treated CLL, GS-1101 (CAL-101) Has Been Evaluated as Monotherapy and in Combination Therapy Phase 1b Combination Study Phase 1b Monotherapy Study Rituximab 375 mg/m 2 weekly C1 and C2 GS to 350 mg BID GS or 150 mg BID GS mg BID Fludarabine 40 mg/m 2 P.O. Days 1 – 5 C1 – C6 GS or 150 mg BID Bendamustine 70 or 90 mg/m 2 Days 1 and 2 C1 – C6 GS mg BID Rituximab 375 mg/m 2 D1 C1 – C6 Bendamustine 70 or 90 mg/m 2 Days 1 and 2 C1 – C Designs:Phase 1-2 dose-ranging trials Endpoints:Recommended dosing regimen, safety, antitumor activity Follow-up:After 48 weeks, patients who continue to benefit can continue GS-1101 single-agent therapy on an extension study

82 a Decrease by  50% in the nodal SPD b Response by IWCLL criteria [Hallek 2008] GS-1101 Combination Therapies Substantially Increased Overall Response Rate G Mono (N=55) Overall Response (OR) b Lymph Node Response (LNR) a LNRORLNRORLNRORLNROR G+R (N=19) G+F (N=7) G+B (N=14) G+R+B (N=14) ITT Response a Rate  95% CI

83 Cycles (4 weeks ) % Progression-free GS-1101 Mono (N=55) G+R G+F (N=19) (N=7) G+B G+R+B (N=14) Both GS-1101 Monotherapy and Combination Therapy were Associated with Durable Tumor Control GS-1101 monotherapy: Median PFS >12 months GS-1101 combination therapy: Median PFS not yet reached

84 Grade  3 Adverse Events (Regardless of Cause) % (n) MonoCombination GS-1101 (N=63) GS R (N=19) GS B (N=20) GS BR (N=13) All Comb. (N=52) Anemia10% (6)5% (1)10% (2) ̶ 6% (3) Neutropenia11% (7) 32% (6)25% (5)23% (3)27% (14) Febrile neutropenia2% (1) ̶ 10% (2) ̶ 4% (2) Thrombocytopenia8% (5)5% (1)15% (3)8% (1)10% (5) ALT/AST elevated22% (14)21% (4)30% (6)* ̶ 19% (10)* Cardiac arrest ̶ 5% (1) ̶̶ 2% (1) Colitis ̶ 5% (1) ̶̶ 2% (1) Fatigue6% (4)5% (1)10% (2) ̶ 6% (3) Pneumonia/Pneumonitis13% (8)11% (2)35% (7) ̶ 17% (9) Rash3% (2)5% (1)10% (2)8% (1)8% (4) Sepsis ̶̶ 5% (1) ̶ 2% (1) * Only 1 pt experienced repeated ALT/AST elevations upon GS-1101 re-exposure Adverse Event Profiles Have Been Generally Consistent with the Known Safety Profiles of Each Agent


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