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

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

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

First-Line DLBCL• DBL3001 - A Randomized, Double-blind, Placebo-controlled Phase

3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, PCI-32765 (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 (NCT01855750)

• 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

Previously Treated DLBCL

• PCYC-1106 - 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) (NCT01325701)

• 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

First-Line FL

• A051103 - A Phase I Study of Rituximab, Lenalidomide, and Ibrutinib in Previously Untreated Follicular Lymphoma (NCT01829568)

• 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

Previously Treated FL

• FLR2002 - An Open-Label, Multicenter, Single-Arm, Phase 2 Study of PCI-32765 (Ibrutinib) in Subjects With Refractory Follicular Lymphoma (NCT01779791)

• 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

First-Line MCL

• MCL3002 - A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, PCI-32765 (Ibrutinib), in Combination With Bendamustine and Rituximab (BR) in Subjects With Newly Diagnosed Mantle Cell Lymphoma (NCT01776840)

• 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

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 (NCT01646021)

• 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

First-Line CLL/SLL >65 years

• PCYC-1115 - 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 (NCT01722487)

• 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

First-Line CLL/SLL

• A041202 - 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) (NCT01886872)

• 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

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 (NCT01611090)

• 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

Previously Treated CLL/SLL

• PCYC-1112 - 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) (NCT0157807)

• 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

Previously Treated CLL/SLL with 17p Deletion

• PCYC-1117 - An Open-label, Single arm, Multicenter Phase 2 Study of the Bruton's Tyrosine Kinase Inhibitor PCI-32765 (Ibrutinib) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma with 17p Deletion (NCT01744691)

• 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

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Phase I in B-NHL

R/R CLL

MCL

R/RR-chemo

FL

MCL 1st line

DLBCL 1st line

PCYC1102PCYC1104

WMPCYC1106

MCL3001

FLR2002DBL3001

MCL3002

PCYC1115

A041202

CLL3001PCYC1112

PCYC1117

WM?

R/R non-GC

DLBCLCLL 1st

line

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?

Ibrutinib Future Challenges

• Adverse events– Bleeding?– Leukocytosis? Is it significant?

• Duration of therapy?

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

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

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 (NCT01351935)

• 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

Previously Treated NHL

• A phase IB study of the BTKi CC-292 combined with lenalidomide in adult patients with relapsed/refractory B-cell lymphomas (NCT01766583)

• 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

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CLEAR

AVL-292-003

CC-292 Future Challenges

• Comparison to ibrutinib– Specific subtypes?– Efficacy?– Safety?

PI3K

BCR

PI3KDelta

CD40

STAT

T308 S473AKT

JAKTRAF6

NF-kpathway

JAK

mTOR

BTK

PLC2

PKC GSK-3

LYN

SYK LYN/SYK

T-cell Signalingstimulus

gp130 gp130

STAT BTK

PLC2

p70s6k elf4E

Malignant B-cell membraneCXCR5

BAFFR

Stromal cell

IL-6R

CXCL13BAFFIL-6

Lannutti, Blood, 2011

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

Rituximab/Alkylator-refractory iNHL

• CAL-101-09 - 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 (NCT01282428)

• 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

Previously Treated iNHL• GS-312-0124 - 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 (01732913)

• GS-312-0125 - 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 (NCT01732926)

• 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

Previously Treated FL

• A051202 - A Phase I Trial of Lenalidomide, Rituximab and Idelalisib in Recurrent Follicular Lymphoma (NCT01644799)

• 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

Previously Treated MCL

• A051201 - A Phase I/Randomized Phase II Trial of Idelalisib, Lenalidomide and Rituximab in Patients With Relapsed/Refractory Mantle Cell Lymphoma(NCT01838434)

• Primary outcome: MTD• Key eligibility: Previously treated MCL• Estimated enrollment: 99• Start date: July 2013, open to accrual• Estimated completion date: August 2017

Previously Treated CLL/SLL

• GS-312-0116 - 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 (NCT01539512)

• 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

Previously Treated CLL/SLL

• GS-312-0115 - 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 (NCT01569295)

• 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

Previously Treated CLL/SLL

• GS-312-0119 - 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 (NCT01659021)

• 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

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CAL-101-09

Phase I

R/RR-alkylator

iNHL

CAL-101-07

0124

0125

R/RiNHL

GS-312-0115

GS-312-0116

GS-312-0119

R/RCLL

Idelalisib Future Challenges

• Adverse effects– Hepatic toxicity– Lymphocytosis

• Mechanisms of resistance– Unclear, no published mutations in PI3Kd

Idelalisib Future Opportunities

• Novel combinations• Ibrutinib resistant patients• Front-line CLL• Front-line iNHL• Aggressive lymphomas

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

Previously Treated iNHL

• IPI-145-02 - A Phase 1 Study of IPI-145 in Patients With Advanced Hematologic Malignancies (NCT01476657)

• 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

Previously Treated iNHL

• IPI-145-06 - A Phase 2 Study of IPI-145 in Subjects With Refractory Indolent Non-Hodgkin Lymphoma (NCT01882803)

• 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

Previously Treated iNHL

• Phase Ib Study of IPI-145 in Combination With Bendamustine, Rituximab or Bendamustine/Rituximab in Hematologic Malignancies (NCT01871675)

• 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

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IPI-145-02

B+R+D

IPI-145-06

Duvelisib Future Challenges

• Comparison to other PI3k inhibitors• Adverse events

– Myelosuppression?– Hepatic toxicity?

SYK

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

Previously Treated B-Cell NHL

• GS-US-339-0102 - A Phase 2, Open-Label Study Evaluating the Efficacy, Safety, Tolerability, and Pharmacodynamics of GS-9973 in Subjects With Relapsed or Refractory Hematologic Malignancies (NCT01799889)

• 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

Previously Treated B-Cell NHL

• GS-US-339-0103 - A Phase 2 of GS-9973 in Combination With Idelalisib in Subjects With Relapsed or Refractory Hematologic Malignancies (NCT01796470)

• 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

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0102

0103

GS-9973 Future

• Challenges– Comparison to fostamatinib

• Opportunities– Combination with idelalisib

Conclusions

• Potential near term FDA approval– 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