1. Kinase Inhibitors in B-cell Lymphomas: What Does the Future Hold?
Peter Martin, MD

2. Bruton’s Tyrosine Kinase (BTK) A critical kinase for lymphoma cell survival and proliferation
BTK is expressed and functional across non-T-cell hematopoietic lineages
BTK functions downstream in a variety of receptors
Essential element of B-cell receptor signaling
Chemokine mediated migration & adhesion
Toll Like Receptor signaling
B-cell tumors may be dependent upon BTK for proliferation and survival

3. Ibrutinib (PCI-32765)
4/2006 – Pharmacyclics acquires Celera’s BTK program
2007 – Publication describing irreversible inhibitors of BTK (including PCI-32765) in ChemMedChem
12/2007 – Poster at ASH describing activity in B-cell lymphoma
2/2009 – Phase I trial in B-NHL initiated
12/2009 – Poster at ASH describing preliminary results from phase I trial
12/8/11 – Pharmacyclics partners with Janssen

4. Ibrutinib (PCI-32765) 1/2013 – Publication of phase I trial in JCO
2/12/13 - FDA grants Breakthrough Therapy Designation for MCL and WM
4/8/13 – FDA grants Breakthrough Therapy Designation for CLL
6/2013 – Publication of two phase II trials (CLL, MCL) in NEJM
8/29/13 – FDA accepts NDA applications for MCL and CLL
>40 trials have been initiated to date in clinicaltrials.gov, 3 publications in peer-reviewed journals

5. First-Line DLBCL
DBL3001 - A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, PCI (Ibrutinib), in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Subjects With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma (NCT )
Primary outcome: EFS
Key eligibility: Stage >2 histologically confirmed non-GC DLBCL, IPI >1, ECOG <2
Estimated enrollment: 800, 218 study locations, international
Start date: August 2013, open to accrual
Estimated completion date: June 2018

6. Previously Treated DLBCL
PCYC A Multicenter, Open-label, Phase 2, Safety and Efficacy Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, in Subjects With Relapsed or Refractory or de Novo Diffuse Large B-cell Lymphoma (DLBCL) (NCT )
Primary outcome: Response rate
Key eligibility: relapsed/refractory non-GC DLBCL (central IHC by Hans method)
Estimated enrollment: 125, 15 sites in US
Start date: May 2011, open to accrual
Estimated completion date: June 2015

7. First-Line FL
A  A Phase I Study of Rituximab, Lenalidomide, and Ibrutinib in Previously Untreated Follicular Lymphoma (NCT )
Primary outcome: MTD
Key eligibility: untreated, stage >2 FL
Estimated enrollment: 33, 5 sites in US
Start date: June 2013, open to accrual
Estimated completion date: January 2014

8. Previously Treated FL
FLR2002 - An Open-Label, Multicenter, Single-Arm, Phase 2 Study of PCI (Ibrutinib) in Subjects With Refractory Follicular Lymphoma (NCT )
Primary outcome: Response rate
Key eligibility: FL, >2 prior lines of therapy, last prior line must be rituximab-chemo regimen, progression within 12 months of last prior line.
Estimated enrollment: 110, 59 sites, international
Start date: April 2013, open to accrual
Estimated completion date: September 2016

9. First-Line MCL
MCL3002 - A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, PCI (Ibrutinib), in Combination With Bendamustine and Rituximab (BR) in Subjects With Newly Diagnosed Mantle Cell Lymphoma (NCT )
Primary outcome: Progression-free survival
Key eligibility: untreated stage >2 MCL
Estimated enrollment: 520, 268 sites, international
Start date: May 2013, open to accrual
Estimated completion date: March 2018

10. Previously Treated MCL
MCL4001 - An Open Label Treatment Use Protocol for Ibrutinib in Subjects With Relapsed or Refractory Mantle Cell Lymphoma (NCT )
Primary outcome: Frequency of adverse experiences
Key eligibility: Previously treated MCL
Estimated enrollment: 250, 57 sites in US
Start date: April 2013, open to accrual
Estimated completion date: May 2014

11. Previously Treated MCL
MCL3001 - A Randomized, Controlled, Open-Label, Multicenter Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, Versus Temsirolimus in Subjects With Relapsed or Refractory Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy (NCT )
Primary outcome: Progression-free survival
Key eligibility: Previously treated MCL, at least 1 prior rituximab-containing regimen
Estimated enrollment: 280, 138 sites outside US
Start date: December 2012, open to accrual
Estimated completion date: August 2014

12. First-Line CLL/SLL >65 years
PCYC  A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor PCI-32765 Versus Chlorambucil in Patients 65 Years or Older With Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (NCT )
Primary outcome: Progression-free survival
Key eligibility: Untreated CLL, age >65
Estimated enrollment: 111
Start date: January 2013, open to accrual
Estimated completion date: June 2015

13. First-Line CLL/SLL
A  A Randomized Phase III Study of Bendamustine Plus Rituximab Versus Ibrutinib Plus Rituximab Versus Ibrutinib Alone in Untreated Older Patients (>65 Years of Age) With Chronic Lymphocytic Leukemia (CLL) (NCT )
Primary outcome: Progression-free survival
Key eligibility: Untreated CLL, Age >65
Estimated enrollment: 523, all Alliance sites in US
Start date: July 2013, not yet recruiting
Estimated completion date: March 2018

14. Previously Treated CLL/SLL
CLL3001 - Randomized, Double-blind, Placebo-controlled Phase 3 Study of Ibrutinib, a Bruton's Tyrosine Kinase (BTK) Inhibitor, in Combination With Bendamustine and Rituximab (BR) in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (NCT )
Primary outcome: Progression-free survival
Key eligibility: Previously treated CLL
Estimated enrollment: 580, 155 sites, international
Start date: September 2012, open to accrual
Estimated completion date: August 2015

15. Previously Treated CLL/SLL
PCYC  The purpose of the study is to evaluate whether treatment with ibrutinib as a monotherapy results in a clinically significant improvement in progression free survival (PFS) as compared to treatment with ofatumumab in patients with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) (NCT )
Primary outcome: Progression-free survival
Key eligibility: Previously treated CLL
Estimated enrollment: 391, international
Start date: June 2012, closed to accrual
Estimated completion date: July 2015

16. Previously Treated CLL/SLL with 17p Deletion
PCYC  An Open-label, Single arm, Multicenter Phase 2 Study of the Bruton's Tyrosine Kinase Inhibitor PCI (Ibrutinib) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma with 17p Deletion (NCT )
Primary outcome: Response rate
Key eligibility: Previously treated CLL, deletion of 17p
Estimated enrollment: 111
Start date: January 2013, closed to accrual
Estimated completion date: March 2016

17. MCL 1st line
DLBCL 1st line
R/R non-GC
DLBCL
CLL 1st line
R/R
CLL
MCL
R/R
R-chemo FL
WM?
Phase I in B-NHL
PCYC1102
PCYC1104
PCYC1106 WM
PCYC1112
CLL3001
MCL3001
PCYC1115
PCYC1117
A041202
FLR2002
DBL3001
MCL3002
‘09
‘10
‘11
‘12
‘13
‘14
‘15
‘16
‘17
‘18

18. Ibrutinib Future Challenges
Patient selection
DLBCL: non-GC
Current trials require central pathology. How will this work in community setting?
Resistance
BTK mutations (C481S). Role for other BTK inhibitors?
Other mutations in CLL: PLCg2
Other mutations in DLBCL: CD79B, not CARD11, MYD88?
Role for rational combinations?

19. Ibrutinib Future Challenges
Adverse events
Bleeding?
Leukocytosis? Is it significant?
Duration of therapy?

20. Ibrutinib Future Opportunities
Other lymphomas
Untreated FL
Compared to R-chemo? Compared to R-len? Added to R-X?
Untreated WM
Compared to R-X?
MZL
HCL

21. AVL-292 (CC-292) 2009- Avila presents data on Btk inhibitors
6/2011 – Phase I trial initiated in B-NHL
3/7/12 – Celgene acquires Avila
11/2012 – Phase Ib plus lenalidomide initiated in CLL
5 trials have been initiated in clinicaltrials.gov, no publications in peer-reviewed journals

22. Previously Treated NHL
Phase 1b, Escalating Dose Study of AVL-292, a Bruton's Tyrosine Kinase (Btk) Inhibitor, as Monotherapy in Subjects With Relapsed and/or Refractory B Cell Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, and Waldenstrom's Macroglobulinemia (NCT )
Primary outcome: Safety
Key eligibility: Previously treated B-cell NHL
Estimated enrollment: 60, 13 sites in US
Start date: June 2011, open to accrual
Estimated completion date: December 2013

23. Previously Treated NHL
A phase IB study of the BTKi CC-292 combined with lenalidomide in adult patients with relapsed/refractory B-cell lymphomas (NCT )
Primary outcome: RP2D
Key eligibility: Previously treated B-NHL except CLL/SLL and WM
Estimated enrollment: 60, 6 sites in France
Start date: February 2013, open to accrual
Estimated completion date: April 2015

24. AVL
CLEAR
‘09
‘10
‘11
‘12
‘13
‘14
‘15
‘16
‘17
‘18

25. CC-292 Future Challenges Comparison to ibrutinib Specific subtypes?
Efficacy?
Safety?

26. Malignant B-cell membrane
PI3K
BCR
PI3K
Delta
CD40
STAT
T308
S473
AKT
JAK
TRAF6
NF-k
pathway
mTOR
BTK
PLC2
PKC
GSK-3
LYN
SYK   
LYN/SYK
T-cell
Signaling
stimulus
gp130
p70s6k
elf4E
Malignant B-cell membrane
CXCR5
BAFFR
Stromal cell
IL-6R
CXCL13
BAFF
IL-6
Lannutti, Blood, 2011

27. Idelalisib (CAL-101, GS-1101)
5/12/05 – Patent filed for PI3Kd inhibitor
06/2008 – Phase I trial initiated
2/22/11 – Gilead acquires Calistoga Pharmaceuticals
9/11/13 – Gilead submits NDA for indolent NHL
10/9/13 – Gilead halts phase III CLL trial, everyone crosses over to idelalisib
16 studies have been initiated in clinicaltrials.gov, no publications in peer-reviewed journals

28. Rituximab/Alkylator-refractory iNHL
CAL A Phase 2 Study to Assess the Efficacy and Safety of CAL-101 in Patients With Indolent B-Cell Non-Hodgkin Lymphoma Refractory to Rituximab and Alkylating Agents (NCT )
Primary outcome: Response rate
Key eligibility: Previously treated FL, SLL, LPL/WM, MZL
Estimated enrollment: 120, 55 sites, international
Start date: January 2011, closed to accrual
Estimated completion date: October 2013

29. Previously Treated iNHL
GS  A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in Combination With Rituximab for Previously Treated Indolent Non-Hodgkin Lymphomas ( )
GS  A Phase 3, Randomized, Double-Blind, Placebo Controlled Study Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in Combination With Bendamustine and Rituximab for Previously Treated Indolent Non-Hodgkin Lymphomas (NCT )
Primary outcome: Progression-free survival
Key eligibility: Previously treated FL, SLL, LPL/WM, MZL
Estimated enrollment: 375/450, >40 sites, international
Start date: December 2012, open to accrual
Estimated completion date: December 2016/April 2016

30. Previously Treated FL
A  A Phase I Trial of Lenalidomide, Rituximab and Idelalisib in Recurrent Follicular Lymphoma (NCT )
Primary outcome: MTD
Key eligibility: Previously treated FL
Estimated enrollment: 30, 6 sites in US
Start date: July 2013, open to accrual
Estimated completion date: November 2013

31. Previously Treated MCL
A  A Phase I/Randomized Phase II Trial of Idelalisib, Lenalidomide and Rituximab in Patients With Relapsed/Refractory Mantle Cell Lymphoma (NCT )
Primary outcome: MTD
Key eligibility: Previously treated MCL
Estimated enrollment: 99
Start date: July 2013, open to accrual
Estimated completion date: August 2017

32. Previously Treated CLL/SLL
GS  A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in Combination With Rituximab for Previously Treated Chronic Lymphocytic Leukemia (NCT )
Primary outcome: Progression-free survival
Key eligibility: Previously treated CLL/SLL, not fit to receive chemo
Estimated enrollment: 200
Start date: February 2012, closed to accrual
Estimated completion date: February 2014

33. Previously Treated CLL/SLL
GS  A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in Combination With Bendamustine and Rituximab for Previously Treated Chronic Lymphocytic Leukemia (NCT )
Primary outcome: Progression-free survival
Key eligibility: Previously treated CLL/SLL
Estimated enrollment: 390
Start date: May 2012, open to accrual
Estimated completion date: October 2015

34. Previously Treated CLL/SLL
GS  A Phase 3, Randomized, Controlled Study Evaluating the Efficacy and Safety of GS-1101 (CAL-101) in Combination With Ofatumumab for Previously Treated Chronic Lymphocytic Leukemia (NCT )
Primary outcome: Progression-free survival
Key eligibility: Previously treated CLL/SLL
Estimated enrollment: 210
Start date: November 2012, open to accrual
Estimated completion date: December 2014

35. R/R
R-alkylator
iNHL
R/R
iNHL
R/R
CLL
Phase I
CAL
CAL GS GS GS
0124
0125
‘09
‘10
‘11
‘12
‘13
‘14
‘15
‘16
‘17
‘18

36. Idelalisib Future Challenges
Adverse effects
Hepatic toxicity
Lymphocytosis
Mechanisms of resistance
Unclear, no published mutations in PI3Kd

37. Idelalisib Future Opportunities
Novel combinations
Ibrutinib resistant patients
Front-line CLL
Front-line iNHL
Aggressive lymphomas

38. Duvelisib (IPI-145) 10/31/11 – Phase I trials initiated
9 studies initiated in clinicaltrials.gov, only 3 in hematologic malignancies, no publications in peer reviewed journals

39. Previously Treated iNHL
IPI A Phase 1 Study of IPI-145 in Patients With Advanced Hematologic Malignancies (NCT )
Primary outcome: Safety
Key eligibility: Previously treated
Estimated enrollment: 250, 7 sites in US
Start date: October 2011,open to accrual
Estimated completion date: September 2014

40. Previously Treated iNHL
IPI A Phase 2 Study of IPI-145 in Subjects With Refractory Indolent Non-Hodgkin Lymphoma (NCT )
Primary outcome: Response rate
Key eligibility: previously treated FL, MZL, SLL, rituximab refractory
Estimated enrollment: 120, 3 sites in US
Start date: May 2013, open to accrual
Estimated completion date: May 2015

41. Previously Treated iNHL
Phase Ib Study of IPI-145 in Combination With Bendamustine, Rituximab or Bendamustine/Rituximab in Hematologic Malignancies (NCT )
Primary outcome: Safety
Key eligibility: Previously treated B-cell NHL
Estimated enrollment: 70
Start date: May 2013, open to accrual
Estimated completion date: June 2014

42. IPI
B+R+D
IPI
‘09
‘10
‘11
‘12
‘13
‘14
‘15
‘16
‘17
‘18

43. Duvelisib Future Challenges
Comparison to other PI3k inhibitors
Adverse events
Myelosuppression?
Hepatic toxicity?

44. SYK

45. GS-9973
2012 – Preclinical data
04/2013 – combination with idelalisib is safe in healthy volunteers
3 trials have been initiated in clinicaltrials.gov, no publications in peer reviewed journals

46. Previously Treated B-Cell NHL
GS-US  A Phase 2, Open-Label Study Evaluating the Efficacy, Safety, Tolerability, and Pharmacodynamics of GS-9973 in Subjects With Relapsed or Refractory Hematologic Malignancies (NCT )
Primary outcome: Progression-free survival
Key eligibility: Previously treated B-NHL
Estimated enrollment: 280, 30 sites in US
Start date: March 2013, open to accrual
Estimated completion date: February 2015

47. Previously Treated B-Cell NHL
GS-US  A Phase 2 of GS-9973 in Combination With Idelalisib in Subjects With Relapsed or Refractory Hematologic Malignancies (NCT )
Primary outcome: Response rate
Key eligibility: Previously treated B-NHL
Estimated enrollment: 200, 11 sites in US
Start date: April 2013, open to accrual
Estimated completion date: December 2015

48. 0102
0103
‘09
‘10
‘11
‘12
‘13
‘14
‘15
‘16
‘17
‘18

49. GS-9973 Future Challenges Opportunities Comparison to fostamatinib
Combination with idelalisib

50. Conclusions Potential near term FDA approval Pivotal trials underway
Ibrutinib: MCL, CLL, WM
Idelalisib: iNHL, CLL
Pivotal trials underway
Ibrutinib: DLBCL, CLL, MCL, FL
Idelalisib: CLL, iNHL
Expect about 5000 patients to be treated on pivotal trials over 5 years
Very limited data in peer-reviewed journals
Opportunities to improve depend on understanding of resistance, so far unclear