1. CLL : Integrating novel therapies into frontline and salvage regimens
Michael Keating M.B.,B.S.

2. New Treatments for CLL - 2011
Lenalidomide , Flavopiridol, SCH
Ofatumumab, GA-101, Abt-263, etc
Bendamustine, Nelarabine
CAL 101(PI3-K Delta inhibitor), BTK Inhibitor, etc
PEITC (Huang), Sapacitabine (Plunkett)
Immuno-therapy (CARs)
OFAR (Oxaliplatin)—Richter’s
8. Non –ablative allo transplant.

3. Frontline therapy for CLL

4. Response to FC + Rituximab (NCI-WG: 300 Patients)
Response # Pts. ( % )
CR (72%)
Nodular PR (10%) %
PR (12%)
No Response ( 4%)
Early Death ( 1%)

5. FCR-300 Survival and Time to Fail
Proportion

6. Is FCR good for everyone ?
Mutation status?
17p– (p53 mutation)?
11q- (ATM deletion)?
Age greater than 70 years? 7

7. Time to Progression FCR Based responders by Mutation Status and FISH 2004-2010
Proportion

8. Time to Fail Untreated CLL Age <70 by FISH (2004-10)
Proportion

9. ELDERLY CLL

10. Response to FCR (Front-Line) by Age, Stage, 2M
Characteristic Value Pts. %CR P value
Age (years) < ≥
Rai Stage 0-II * 0.002
III-IV
2Microglobulin <
< 0.001 ≥
Tam CS, et al, Blood. 112(4): , 2008 Aug 15 11

11. Survival CLL Patients Age >70 by Rx
Proportion

12. First-line Rituximab + Chlorambucil for Elderly: Response after induction
Response (85 patients)
N (%)
ORR
69 (81) CR
14 (16)
CRi
2 (2)
nPR
PR,Cri, NPR
51 (60) SD
4 (4) PD
3 (3)
Withdrew
9 (10)
Foà, et al. ASH 2011, Abstract 294

13. Lenalidomide as Initial Treatment of Elderly Patients
Phase II, 60 patients
Frontline patients with standard indications for treatment
Age 65 years or older
5 mg orally daily for 56 days,  5 mg/28 days  max 25 mg daily
Allopurinol 300 mg day as tumor lysis syndrome prophylaxis
Based on the activity in previously treated patients, we investigated lenalidomide as initial therapy of elderly patients. This trial completed enrolment in april 2009
Badoux, X et al. (submitted)

14. Lenalidomide in Elderly CLL: Response (2008 NCI-WG Criteria)
NCI Response
n patients %
CR* 6 10
CRi* 3 5
Nodular PR PR 25 42
ORR 37 62
Responses according to the 2008 criteria are shown here. ORR was 62%, 10 % CR, 5% Cri, 5% nod PR, 42% PR
*4 patients (8%) with flow cytometry negative CR
Badoux, X et al. (submitted)

15. Lenalidomide in Elderly CLL: Serum Immunoglobulins (n=37)
Would take out the 30 under 21 cycles…it gets confusing
Cycles of therapy
Cycles of therapy
8/16 (50%) patients with IgG<600mg/dl → normalized serum IgG

16. Lenalidomide in Elderly CLL: Hematological Toxicity
Toxicity as % of cycles
Grade 3
Grade 4
Neutropenia 24 10
Thrombocytopenia 11
<1
Anemia
The most commonly observed Grade 3 or 4 toxicity occurring with lenalidomide therapy was hematological. As the drug is administered continuously, cytopenias were listed as a proportion of treatment cycles and were analyzed utilizing the NCI working group criteria for toxicity in CLL. Grade 3 or 4 neutropenia occurred in 38% of treatment cycles and grade 3 or 4 thrombocytopenia occurred in 14% of treatment cycles. These cytopenias generally responded to dose reduction or interruption and were reversible.
*NCI-working group criteria
Badoux, X et al. (submitted) 17

17. Lenalidomide in Elderly CLL: Overall and Progression-free Survival
Proportion

18. Lenalidomide + Rituximab in First-line CLL Progression-free Survival
Arm A (< 65 years)
n=40 patients
16 events
Median PFS: 19 months
Median follow-up: months
Arm B (≥ 65 years)
n=29 patients
13 events
Median PFS: 20 months
Median follow-up: months
Patients (%) 20 40 60 80
100
PFS (months) 2 4 6 8 10 12 14 16 18 22 24
Arm A
Arm B
PFS was defined as the time from when patients started treatment to when the disease progressed or to death, or censored on the last known alive date for patients who are still on study.
Patients who went off study due to toxicity or initiated a new therapy were censored on the date they went off study.
James, et al. ASH 2011, Abstract 291 19

19. Lenalidomide + Rituximab in Relapsed CLL Best Responses
NCI-WG Response
n patients %
CR* 7 12
Nodular PR PR 25 42
ORR 39 66
* MRD-negative CR = 2
Badoux, et al. ASH 2011, Abstract 980

20. Lenalidomide + Rituximab in Relapsed CLL Responses by Pre-treatment Characteristic
ORR (%)
Rai Stage
I–II 31 71
III–IV 28 54
Bulky
< 5 cm 49 67
≥ 5 cm 10 40
FISH
13q deletion 9
(N = 58)
Negative 11 55
Trisomy 12 7
11q deletion 16 69
17p deletion 15 53
Fludarabine
Not refractory 47 70
Refractory 12
33*
* Fisher’s exact test p < 0.05
Badoux, et al. ASH 2011, Abstract 980

21. Lenalidomide + Rituximab in Relapsed CLL Overall and Progression-free Survival
Median follow-up 31 months:
Overall Survival
75%
(95%CI: 64-87%)
Median PFS
17.4 months
(95%CI: )
Total
Failed / Died OS 59 14
PFS 42
Badoux, et al. ASH 2011, Abstract 980

22. Phase II of Lenalidomide + Ofatumumab for Relapsed CLL (N=34)
Day 9: Lenalidomide 10 mg daily until progression
Ofatumumab 300 mg
Ofatumumab 1000mg
Ofatumumab 1000mg
Ofatumumab 1,000mg
Days 1 1
Months 1
2-6
8-24 (every other month)
Concomitant Treatments:
Allopurinol 300 mg day of cycle 1
No antibiotic or anti-viral prophylaxis, no mandated DVT prophylaxis
Ferrajoli, et al. ASH 2011, Abstract 1788

23. Phase II of Lenalidomide + Ofatumumab for Relapsed CLL – Responses (N=34)No %
Complete Response 4 12
CRi* 1 3
Partial Response 17 50
Overall Response 22 65
Stable Disease
Failure 9 26
Discontinuation 2 6
Ferrajoli, et al. ASH 2011, Abstract 1788

24. NEW AGENTS FOR CLL

25. Untreated CLL: Chlorambucil vs Bendamustine Progression-Free Survival
Knauf WU, et al. Blood. 2007:110. Abstract 2043 and poster at American Society of Hematology Annual Meeting 2007. 26

26. Bendamustine +Rituximab Treatment Schedule
B = Bendamustine 90 mg/m2 day 1-2, cycle 1-6, q4wks
R = Rituximab 375 mg/m2 day 0, cycle 1,
500 mg/m2 cycle 2-6, q4wks

27. Bendamustine + rituximab-- Ph 11 CLL2M Frontline therapy for CLL
Patients
CR (%) (23%)
PR (%) (63%)
Median EFS months
Fischer et al. ASH 2009; Abstract 205

28. B CELL RECEPTOR SIGNALING

29. B Cell Receptor Signaling Pathway
Therapeutic targets for small molecule inhibitors:
PI3K
BTK
LYN
SYK

30. CORPORATE OVERVIEW
Single-Agent CAL-101 Resulted in Nodal Shrinkage in All Evaluable Patients with CLL
October 19
Furman et al. ASH 2010, Abstract 55 31

31. CAL-101 (C) Combination Therapies Substantially Increased Overall Response Rate
Adverse event profiles were generally consistent wit the known safety profiles of each agent
CAL-101 Mono
(N=55)
C+R
(N=19)
C+F
(N=7)
C+B
(N=14)
C+R+B
(N=14)
ITT Response Rate
Although lymph node response were comparable in different treatment groups,
combining CAL-101 with
rituximab
Or bendamustine significantly improved the overall response
Overall Response
(OR)b
Lymph Node Response
(LNR)a
LNR OR
LNR OR
LNR OR
LNR
O R
a Decrease by 50% in the nodal SPD
b Response by IWCLL criteria [Hallek 2008]
Sharman, et al. ASH 2011, Abstract 1787

32. Both CAL-101 (GS-1101) Monotherapy and Combination Therapy were Associated with Durable Tumor Control
C+R
(N=19)
C+B
(N=14)
CAL-101
Mono
(N=55)
C+F
(N=7)
C+R+B
(N=14)
% Progression-free
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 CAL-101 basically abolishes the ALC elevation, the difference between the curves is less significant.
Cycles (4 weeks)
Sharman, et al. ASH 2011, Abstract 1787

33. PCI-32765 Novel Small Molecule Btk Inhibitor
Forms a specific and irreversible bond with cysteine-481 in Btk
Potent Btk inhibition
IC50 = 0.5 nM
Orally available N H 2 O
PCI-32765
Burger et al. ASH 2010, Abstract 57

34. Cumulative Best Response 420 mg/d cohort (n=27)
67%
59%
56%
56%
48%
Response Rate %
41%
34%
33%
22%
19%
Cycle 2
Cycle 5
Cycle 8
Cycle 11
Best Response CR PR
Nodal Response
O’Brien, et al. ASH 2011, Abstract 983

35. Maximum % Change in LN Disease
% Change in LN Dimensions
The next few slides will describe the characteristics of response to PCI
As measured by CT scan every 2 months, patients treated with PCI typically had an immediate and marked nodal response to treatment, expressed here as reduction in aggregate lymph node size. in the 39 patients in this series with evaluable nodal disease, 87% of patients have achieved a nodal response. There have been no cases of primary lymph node progression.
(NOTE: 15 patients are not included in this graph: Patients who had normal node size (< 1 cm) (N=5); patients who were TETE (N=5); ;N=4 discontinued before post-treatment measurements were taken and N=1 was a clinical PD.)
34 out of 39 evaluable pt had a nodal response = 87% 36

36. Best Response by Risk Features
n/N
ORR %
All Patients
41/61 67
≥ 70 years age
13/19 68
Bulky disease ≥ 5 cm
24/33 73
Bulky disease ≥ 10 cm
7/10 70
Hgb < 11 g/dL or PLT < 100K/μL at screening
22/36 61
IgVH unmutated
31/42 74
Del 17p
13/20 65
Del 11q
16/22
β2 Microglobulin > 3mg/L
19/29 66
Purine Analog Refractory (< 12 mos from any purine analog to next therapy)
17/28
O’Brien, et al. ASH 2011, Abstract 983

37. ALC versus LN Response: Continuous Dosing
Absolute Lymphocyte Count
pre-treatment
… the “saw-tooth” pattern of lymphocytosis tends to disappear with the continuous daily dosing schedule, as illustrated in this individual case from the Phase 1B/II trial. The absence of a “saw-tooth” pattern in patients receiving PCI continuously suggests a continuous inhibition of lymphocyte homing.
The characteristic rapid nodal response with initial lymphocytosis, and subsequent lymphocyte normalization, is again evidenced, with a smoother rise and fall of circulating lymphocytes. This case also illustrates the difficulty of applying the standard CLL response criteria to this class of agents. While this patient has experienced a major nodal response and symptomatic improvement, the circulating lymphocyte count while continuing to decrease over time has not yet decreased to 50% below baseline. For this reason, he does not yet meet criteria for overall partial response. Since many of the patients in the current series, with limited follow-up, meet this description, we will refer to a category not presently included in the standard response criteria, “nodal response with lymphocytosis”, to characterized this observation.
2 months on treatment

38. NEW ANTIBODIES

39. Ofatumumab in refractory CLL Objective responses by IRC evaluation
51%*
44%*
95% CI
H0: ORR = 15%
*P< versus H0 (two-sided exact test)
CI, confidence interval
Wierda et al. ASH 2010, Abstract 921 40

40. CLL 5 year + 10 year Time to Fail by Decade
Proportion