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

2. Speakers Bureau: GSK, Millenium, Cephalon
Disclosures
Speakers Bureau: GSK, Millenium, Cephalon

3. CLL: Pertinent Topics ASH treatment updates FCR treatment expectations
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 vs. > 65 yrs
Secondary endpoints
Safety, ORR, PFS
CLL, chronic lymphocytic leukemia; CR, complete response; ORR, overall response rate; PFS, progression-free survival.
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
Rituximab
50 mg/m2 on Day 29 of C 1
325 mg/m2 on Day 31 of C 1
375 mg/m2 on Day 33 of C 1
375 mg/m2/wk x 4 for cycle 2
375 mg/m2 on Day 1 of C 3-7
Lenalidomide
Day 1: Starting dose: mg/day
Day 8: Escalated to 5 mg/day
Day 1 cycle 3: increase to mg/day
CLL, chronic lymphocytic leukemia.
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
James DF, et al. ASH Abstract 291.

6. Rituximab + Lenalidomide for Patients With Previously Untreated CLL: Efficacy
Outcome
Younger Than 65 Yrs (n = 40)
65 Yrs or Older (n = 29)
ORR, % CR
CRi
Nodular PR PR 95 20 55 78 7 4 68 PD
Median PFS, mos
Median follow-up 19 18 17
CLL, chronic lymphocytic leukemia; CR, complete response; CRi, CR with incomplete hematopoietic recovery; ECOG, Eastern Cooperative Oncology Group; ORR, overall response rate; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.
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.

7. Rituximab + Lenalidomide for Patients With Previously Untreated CLL: Toxicity
AEs, %
Younger Than 65 Yrs (n = 40)
65 Yrs or Older (n = 29)
Any toxicity
Grade 1/2
Grade 3/4 33 65 17 69
Nonhematologic toxicity 63 35 38 45
Tumor flare reaction No
Yes 18
83* 41 59
AE, adverse event; CLL, chronic lymphocytic leukemia.
*P = .05 vs older patients.
James DF, et al. ASH Abstract 291.

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
observation
Chlorambucil 8 mg/m2/day
Days 1-7
PR, CR
Rituximab
375 mg/m2 Day 1 of cycle 3
500 mg/m2 on Day 1 > C4
R 375 mg/m2
8 wks for 12 doses
CLL, chronic lymphocytic leukemia; ORR, overall response rate; R-FC, rituximab/fludarabine/cyclophosphamide.
Foa R, et al. ASH Abstract 294.

9. ML21445: Responses Response Following Induction, % Patients (ITT)
ORR
All patients
81.2
Binet stage A
86.0
Binet stage B
80.0
Binet stage C
79.0
60-64 yrs of age
84.0
65-69 yrs of age
85.0
70-74 yrs of age or older
75.0
75 yrs of age
81.0
Response Following Induction, %
Patients (ITT)
(N = 85)
CR/CRi 19 PR
60.0 PD
3.5
CLL, chronic lymphocytic leukemia; CR, complete response; CRi, CR with incomplete bone marrow recovery; ITT, intent to treat; MRD, minimal residual disease; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.
*By flow cytometry.
Foa R, et al. ASH Abstract 294.

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)
CLL, chronic lymphocytic leukemia; IgVH, immunoglobulin heavy-chain variable region.
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
AE, adverse event; CLL, chronic lymphocytic leukemia; SAE, serious adverse event.
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 β2-microglobulin or high WBC count not predictive of short PFS
CLL, chronic lymphocytic leukemia; FC, fludarabine, cyclophosphamide; FCR, fludarabine, cyclophosphamide, rituximab; IgVH, immunoglobulin heavy-chain variable region; MRD, minimal residual disease; OS, overall survival; PFS, progression-free survival; WBC, white blood cell.
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 > 10-2 or
MRD levels > 10-4 to < 10-2 plus either
del(17p), TP53 mutation, or IgVH unmutated status
CLL, chronic lymphocytic leukemia; FCR, fludarabine, cyclophosphamide, rituximab; GCLLSG, German CLL Study Group; HR, hazard ratio; IgVH, immunoglobulin heavy-chain variable region; MRD, minimal residual disease; OS, overall survival; PFS, progression-free survival.
Fink A, et al. ASH Abstract 977.
1.. 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)
CI, confidence interval; CLL, chronic lymphocytic leukemia; FCR, fludarabine, cyclophosphamide, rituximab; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.
Fink A, et al. ASH Abstract 977.

15. Lenalidomide + Rituximab Combination in Relapsed/Refractory CLL: Efficacy
Outcome
Patients (N = 59)
Clinical best response, %
ORR 66
CR* 12
Nodular PR PR 42
36-mo OS, % (95% CI)
75 (64-87)
Median PFS, mos (95% CI)
17.4 ( )
CI, confidence interval; CLL, chronic lymphocytic leukemia; CR, complete response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response.
*Minimal residual disease-negative CR.
Badoux XC, et al. ASH Abstract 980.

16. Lenalidomide + Rituximab Combination Therapy in Relapsed/Refractory CLL
Patients with relapsed/refractory CLL (N = 59)
Treatment protocol: 28-day cycles
Rituximab 375 mg/m2
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
CLL, chronic lymphocytic leukemia; ITT, intent to treat; ORR, overall response rate.
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)
ATM, ataxia telangiectasia mutated gene; CLL, chronic lymphocytic leukemia; FISH, fluorescence in situ hybridization; ORR, overall response rate; PFS, progression-free survival.
Badoux XC, et al. ASH Abstract 980.

18. Lenalidomide + Rituximab Combination in Relapsed/Refractory CLL: Toxicity
Grade 3/4 AEs, n (%)
Patients (N = 59)
Neutropenia
43 (73)
Thrombocytopenia
20 (35)
Anemia
9 (15)
Any infection
14 (24)
Pneumonia/bronchitis
6 (10)
Febrile neutropenia
Hypercalcemia*
1 (2)
Gastrointestinal
3 (5)
Tumor lysis
VTE
Pain
Weakness
Arrhythmia
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
AE, adverse event; CLL, chronic lymphocytic leukemia; VTE, venous thromboembolism.
Badoux XC, et al. ASH Abstract 980.

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
CLL, chronic lymphocytic leukemia; CR, complete response; FCR, fludarabine, cyclophosphamide, rituximab; MRD, minimal residual disease; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; R-FC, rituximab/fludarabine/cyclophosphamide; SLL, small lymphocytic lymphoma.

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. Phase I Cal-101 (GS-1101) Patient Demographics
Characteristics
N=55
Sex, males/females, %
82/18
Age, median[range], years
63 [37-82]
Bulky adenopathy (5 cm), % 82
Adverse genetics, % del(17p) 31
Relapsed/refractory disease, %
29/71
Prior therapies, median [range], n
5 [2-15]
Prior therapy type, %
Fludarabine
100
Rituximab 98
Alkylating agent 87
Alemtuzumab 33

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

25. Patient B.C. Diagnosed with CLL in 2002
70 year old man with relapsed bulky CLL
Since 2005:
8 treatment regimens
2010 progressive disease

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

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)
Susan O'Brien, MD1, Jan A. Burger, MD, PhD1, Kristie A. Blum, MD2, Richard R. Furman, MD3, Steven E. Coutre, MD4, Jeff Sharman, MD5, Ian W. Flinn, MD, PhD6, Barbara Grant, MD7, Nyla A. Heerema, PhD2, Amy J. Johnson, PhD2, Tasheda Navarro8, Eric Holmgren, PhD8, Eric Hedrick, MD8 and John C. Byrd, MD2
1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Division of Hematology and The Department of Pathology, The Ohio State University, Columbus, OH
3Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY
4Divisions of Hematology and Oncology and Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA
5US Oncology, Springfield, OR
6Sarah Cannon Research Institute, Nashville, TN
7Medicine, Vermont Cancer Center, University of Vermont, Burlington, VT
8Pharmacyclics, Inc, Sunnyvale, CA

31. Total enrollment 117 patients
PCYC-1102-CA
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)
9/25 (36)
18/31 (58)
10 (29)
12 (35)
20/32 (63)
35/56 (63)
19 (31)
20 (33)
29/57 (51)
ECOG Performance Status, # (%)
1/2
11 (41)
16 (59)
13/33 (39)
20/33 (61)
24/60 (40)
36/60 (60)
Refractory, # (%)
10 (37)
27 (44)
Bulky Disease, # (%) ≥ 5 cm ≥ 10 cm
13 (48)
1 (4)
20 (59)
9 (26)
33 (54)
10 (16)

33. Best Response ORR* 67% 68% 420 mg/d (N=27) 840 mg/d (N=34) TotalCR
1 (4)
0 (0)
1 (2) PR
17 (63)
23 (68)
40 (66)
ORR*
67%
68%
Nodal
6 (22)
8 (24)
14 (23) SD
1 (3)
2 (3) PD NE
2 (6)
3 (5)
*Per IWCLL 2008 criteria

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

35. Pattern of Response: Blood Lymphocytes vs Lymph Nodes

36. Best Response by Risk Features
n/N
ORR %
All Patients
41/60 68
Hgb < 11 g/dL or PLT < 100K/μL at screening
35/60 58
Del 17p
12/18 67
Del 11q
14/20 70
IgVH unmutated
26/35 74
β2 Microglobulin > 3mg/L
19/29 66
≥ 70 years age
13/18 72
Refractory disease
17/26 65
Bulky disease ≥ 5 cm
24/33 73
Bulky disease ≥ 10 cm
7/10

37. Progression-free Survival by 17p Del Status

38. Common AEs (All Grades) Events occurring in > 15% of Patients (n=61)

39. Grade 3/4 Infectious and Hematologic Toxicity
Grade 3/4 Hematology toxicity 1
420 mg/d
(n=27)
840 mg/d
(n=34)
Neutropenia
Anemia
Thrombocytopenia
Grade 3 Grade 4
4% %
7% %
0% %
12% %
9% %
9% %
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%)
1 Reported as AEs

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 in CLL at OHSU Can we predict who will respond to treatment?
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

42. C-F: Response to treatment
C-F pretreatment scan
C-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 R-Cladribine Based Treatment
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
18 months
MCL: Poor Prognosis and Long-Term Outcome
The German Low Grade Lymphoma Study Group initiated a randomized trial (128 patients) comparing R-CHOP with CHOP as first-line therapy.1
R-CHOP was superior to CHOP in terms of:
Overall response rate 94% vs 75%; P=.0054)
Complete response rate (34% vs. 7%; P=.00024)
Time to treatment failure (median 21 vs 14 months; P=.0131).1
However, induction therapy with R-CHOP did not translate into prolonged PFS vs CHOP (P=0.31).1
In addition, there were no significant differences observed for overall survival.
Along with R-HyperCVAD, R-CHOP is considered a standard of care for the initial treatment of MCL patients.2
R-CHOP is listed in NCCN guidelines as a treatment option for front-line MCL. R-EPOCH and R-HyperCVAD are also listed in NCCN guidelines for initial treatment of MCL.2
References
Lenz G, et al. J Clin Oncol. 2005:23;
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Non-Hodgkin’s Lymphomas. V
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)
Lenz G. et al. J Clin Oncol. 2005;23:

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

48. R-Maintenance SAKK[1] GLSG[2] Modified R-HyperCVAD[3]
 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
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. First RCT for MCL Elderly 8 countries, n = 560 (Jan 2004-Oct 2010)
European MCL Network
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
8 x R-CHOP
6 x R-FC
PR, CR
IFN-a maintenance
(3 x 3 M IU/week)
or Peg-IFN
(1mg/kg week)
Rituximab
maintenance
(all 2 months)

51. MCL Elderly: Baseline Characteristics 1st randomization
Parameter
R-CHOP (%)
R-FC (%)
Age median (range)
70 (61-87)
70 (60-85)
% male 68 72
Stage IV 83 81
% pos. BM 76 75
B-Symptoms 38
Performance 0-1 92 93
Elevated LDH 44 43
MIPI low risk 7 9
MIPI intermediate risk 39
MIPI high risk 50 52 n
280

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

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

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

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

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

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,MD1, David F. Claxton, MD2,
W. Christopher Ehmann, MD2, Samir S. Parekh, MD,3 Violetta Leshchenko, PhD3, Motomi Mori, PhD2, Sara Shimko, BA,2 August Stewart, BA,2 Elliot M. Epner, MD PhD2
Knight Cancer Institute at Oregon Health & Science University, Portland, OR
Penn State Hershey Cancer Institute, Hershey, PA
Albert Einstein College of Medicine, Bronx, NY

61. Study Rationale Cladribine has cytotoxic and epigenetic properties
Vorinostat (SAHA):
inhibits class I and II histone de-acetylases (HDAC)
has shown clinical activity in B-cell lymphomas1
increases tumor suppressor gene expression when combined with a hypomethylating agent2-4
Cladribine and HDAC inhibition are synergistic as evidenced by increased in vitro apoptosis in primary CLL cells.5
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 Responses were seen in MCL and SLL
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)
Population
Total
ITT Overall Response (%)
MCL 10
2 (20%)
2 CR
MZL 3
2 (66%)
1 CR, 1 PR FL 1
1 PR (100%)
Relapsed CLL
NHL Response by Modified Cheson Criteria
CLL Response by IWCLL Criteria

67. Phase II: Previously Untreated Mantle Cell Cohort ( n=21)
Median Age (range) ( 42-87)
Characteristic
Number 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%)
6 (29%)
* Mantle Cell International Prognostic Index

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

69. Phase II Toxicity: Most Prevalent Adverse Events
Frequency (158 treatment cycles)
Hematologic
Neutropenia
Thrombocytopenia
Anemia
Gr Gr. 4
50 (32%) (11%)
32 (20%) (5%)
8 (5%)
Non Hematologic
Fatigue
Infection
Grade 5 Pulmonary Hemorrhage
6 (4%)
3 (2%)
1 (1%)
For both relapsed and untreated cohorts

70. Study currently enrolling patients at OHSU

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
CCL3/4 function: potent T cell chemokines that are secreted by normal B cells during GC reaction to attract T cells

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):563-74
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)
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
Reference: Sharman, ASH 2011, #1787

81. In Previously Treated CLL, GS-1101 (CAL-101) Has Been Evaluated as Monotherapy and in Combination Therapy
Phase 1b
Monotherapy
Study
Phase 1b
Combination Study
GS to 350 mg
BID
GS or 150 mg
BID
GS mg
BID
GS or 150 mg
BID
GS mg
BID + + + +
Rituximab 375 mg/m2 weekly
C1 and C2
Fludarabine 40 mg/m2 P.O.
Days 1 – 5
C1 – C6
Bendamustine 70 or 90 mg/m2
Days 1 and 2
C1 – C6
Rituximab 375 mg/m2 D1
C1 – C6 +
Bendamustine 70 or 90 mg/m2
Days 1 and 2
C1 – C6
Switching gears now and taking a closer look at the GS-1101 experience in patients with previously treated CLL.
Treatment parameters were the same as in patients with iNHL
a single-agent dose-ranging study with doses from 50 mg to 350 mg BID and
- a combination with either rituximab or bendamustine at the same doses for pts with iNHL.
Here also, benefitting pts could roll over to an extension study in order to receive single-agent GS-1101 at the highest dose previously tolerated.
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 single-agent therapy on an extension study 81

82. ITT Responsea Rate 95% CI
GS-1101 Combination Therapies Substantially Increased Overall Response Rate
ITT Responsea Rate 95% CI
G Mono
(N=55)
G+R
(N=19)
G+F
(N=7)
G+B
(N=14)
G+R+B
(N=14)
LNR OR
LNR OR
LNR OR
LNR OR
Overall Response
(OR)b
Lymph Node
Response
(LNR)a
Although lymph node response were comparable in different treatment groups,
combining GS-1101 with
rituximab
Or bendamustine significantly improved the overall response
a Decrease by 50% in the nodal SPD
b Response by IWCLL criteria [Hallek 2008] 82

83. GS-1101 combination therapy: Median PFS not yet reached
Both GS-1101 Monotherapy and Combination Therapy were Associated with Durable Tumor Control
GS-1101 Mono
(N=55)
G+R
G+F
(N=19)
(N=7)
G+B
G+R+B
(N=14)
% Progression-free
Cycles (4 weeks)
This is relevant in a greater scheme:
The Kaplan-Meyer plots here document the PFS for the different treatment groups.
The solid curve represents the actual PFS
The dotted curve the hypothetical data, if the early and transient lymphocytosis would have been interpreted as progression
Since addition of bendamustine to GS-1101 basically abolishes the ALC elevation, the difference between the curves is less significant.
GS-1101 monotherapy:
Median PFS >12 months
GS-1101 combination therapy:
Median PFS not yet reached 83

84. Adverse Event Profiles Have Been Generally Consistent with the Known Safety Profiles of Each Agent
Grade 3 Adverse Events
(Regardless of Cause)
% (n)
Mono
Combination
GS-1101
(N=63)
GS R (N=19)
GS B (N=20)
GS BR (N=13)
All
Comb.
(N=52)
Anemia
10% (6)
5% (1)
10% (2) ̶
6% (3)
Neutropenia
11% (7)
32% (6)
25% (5)
23% (3)
27% (14)
Febrile neutropenia
2% (1)
4% (2)
Thrombocytopenia
8% (5)
15% (3)
8% (1)
10% (5)
ALT/AST elevated
22% (14)
21% (4)
30% (6)*
19% (10)*
Cardiac arrest
Colitis
Fatigue
6% (4)
Pneumonia/Pneumonitis
13% (8)
11% (2)
35% (7)
17% (9)
Rash
3% (2)
8% (4)
Sepsis
* Only 1 pt experienced repeated ALT/AST elevations upon GS-1101 re-exposure
Patients had a median age of with some pts in their late 30s or 40s
The majority of pts in all treatment groups had bulky disease,…
…and refractory disease was present in the majority of pts in the single-agent group…
…as well as in the group receiving combination treatment with bendamustine
The amount of prior therapies was high especially in the single-treatment group, with a range up to 15 prior therapies
As seen with iNHL virtually all the pts have had prior therapies containing rituximab
and many have had previous treatments with bendamustine 84