dr. goy mcl

Andre Goy, MDChairman and Director John Theurer Cancer Center

Lymphoma Program HeadProfessor of Medicine UMDNJ

Mantle Cell Lymph oma

“Novel Therapies”

1st International Educational Symposium

on Mantle Cell Lymphoma

Disclosure

Celgene, Millennium, Pharmacyclics: Research support (clinical trials).

11/11/11

On 11.11.11, the time and date will be a perfect same-numbered palindrome - reading the same backwards as forwards - an event which can only happen on one day every 100 years….

11/11/11

Doomsday...?

More weddings...

New spiritual Era ?

Good luck??

Special Dates

in the Maya Calendar ….

"They were actually preparing for this catastrophe by buying real estate on high places and by stocking up on whatever the 16th-century equivalent of duct tape and bottled water was,"

John Hoopes, Maya History Scholar….

Our sponsors and organizing committee

All my co-investigators and colleagues

All patients and families

All staff nurses and beyond…

The entire TEAM without whom

we COULD NOT do what we DO!!!

- MCL responds to initial therapy but a large proportion of patients relapse

- Dose-intensive therapies / high dose therapies have improved PFS in excess of 5 years

- MCL develops commonly over time chemoresistance

Mantle Cell LymphomaMantle Cell Lymphoma

- Challenging nature of disease has pushed clinical research

- Continue effort in clinical TRIALS ++++

- Considerable progress in biology of MCL new targets

Mantle Cell Lymphoma as a GREAT TEACHERMantle Cell Lymphoma as a GREAT TEACHER

MCL median OS has improved

(from 2.5y to > 5y) over last 2 decades

- Better induction therapy

- Deeper quality of 1st response (molecular CR)

- Maintenance strategies ?

- BETTER salvage therapies / options +++

MCL – Improved Outcome!!!MCL – Improved Outcome!!!

MCL Remains a Challenge in the Relapse Setting


FFS

Poor outcome with conventional cytotoxics

Med duration of response ≈ 6ms with “regular” chemo regimens

29 pts

Classic R-HyperCVAD

Wang, Cancer Nov 2008

HDT- ASCT much << in relapse setting

Tam, Blood April 2009

Addition of rituximab beneficial only frontline setting



New Cytotoxics

New Cytotoxics

New Cytotoxics: BendamustineNew Cytotoxics: Bendamustine

Leoni, Sem Hematol, April 2011

Strong alkylating agent

Developed in Germany in the mid-twentieth century


Ohamchi, Cancer Science Sept 2010

69 pts (11 MCL) Japan

MCL: ORR 100% / 73% CR-CRu

Bendamustine (120 mg/m(2) ) days 1-2 of a 21-day cycle x 6 cycles

At a median follow up of 12.6 months, median PFS not reached


Robinson, JCO Sept 2008

B + R in relapsed indolent B-cell NHL and MCL

Rituximab: day 1: 375mg/m2 + Bendamustine (90 mg/m(2) ) days 2&3 28-day cycle x 6 cycles

SubtypeNo. of

Patients ORR (%) CR (%) CRu (%) PR* (%) SD (%) PD (%)

Total 66 92 41 14 38 8 0

Pathologic subtype Indolent NHL

54 93 41 13 39 7 0

MCL 12 92 42 17 33 8 0

Rituximab exposure Prior rituximab

37 87 35 14 38 14 0

No prior rituximab

29 100 48 14 38 0 0

STiL: First-line Bendamustine + Rituximab in Pts With FL, MCL, MZL

Rummel MJ, et al. ASH 2009. Abstract 405.

Bendamustine-Rituximab (n = 260)B 90 mg/m2 day 1 and 2

R 375 mg/m2 day 1Max 6 cycles, q 4 weeks

R-CHOP (n = 253)Max 6 cycles, q 3 weeks

Stage III or IV CD20+ NHL

(N = 549)

90 MCL pts subset

STiL Trial: PFS (Primary Endpoint)

B-R superior to R-CHOP for PFS in overall (54.9 vs 34.8 mos, P = .00012)

In sub-analysis, B-R superior to R-CHOP in MCL (P = .0146)

Rummel MJ, et al. ASH 2009. Abstract 405.

0.0

0.2

0.4

0.6

0.8

1.0

0 7248352412 60

0.1

0.3

0.5

0.7

0.9

B-RR-CHOP

MCL

P = .0146

Parameter B-R R-CHOP p value

CR, % 39.6 30.3 .026

TTNT, mos NR 37.5 .001

Also favorable toxicity profile

New Biologicals (also called targeted

agents)

New Biologicals (also called targeted

agents)

Targeting the Proteasome Targeting the Proteasome

Ruschak A M et al. JNCI J Natl Cancer Inst 2011;103:1007-1017

Yewdell, Nat Immunl. Rev 3, 952-961

Aaron Ciechanover Avram Hershko Irwin Rose

Nobel Prize in Chemistry 2004

The Ubiquitin–proteasome PathwayThe Ubiquitin–proteasome Pathway

Through this pathway, the cell gets rid

of excess / redundant proteins

and misfolded / abnormal proteins

and regulates biological processes

(homeostasis).

Through this pathway, the cell gets rid

of excess / redundant proteins

and misfolded / abnormal proteins

and regulates biological processes

(homeostasis).

The Ubiquitin–proteasome PathwayThe Ubiquitin–proteasome Pathway

- 30000 proteasomes per cell

- MAIN way to degrade / recycle intra cellular proteins

- 1/3 proteins have ½ life 10mn !!

5% our entire cellular proteins renewed each day!

Yewdell, Nat Immunl. Rev 3, 952-961

Initially studied to understand protein degradation process

Wide range of natural products can inhibit proteasome

Several PI have been developed peptidomimetic that can compete with enzymatic sites

Bind (reversibly or not) catalytic sites (“jammed proteasome”)

Proteasome InhibitorsProteasome Inhibitors

Sites of action of proteasome inhibitorsSites of action of proteasome inhibitors


Chemical structure

Name Type Developer Route of administration

Devlpt. status

Bortezomib Reversible Millennium: The Takeda Oncology Company

IV FDA approved

CEP-18770 Reversible Cephalon IV, oral Phase IMLN-9708 Reversible Millennium:

The Takeda Oncology Company

IV, oral Phase I

Carfilzomib Irreversible Onyx IV Phase Ib

ONX 0912 Irreversible Onyx Oral Phase I

NPI-0052 Irreversible Nereus IV Phase I

Proteasome InhibitorsProteasome Inhibitors


Microenvironment↓ NF-B, ↓ cytokines,↓ cell adhesion molecules,↓ VEGF, ↓ TNF-α

Apoptosis↑ p53, ↑ p21, ↑ Bax,↑ tBID, ↑ Bcl-2,↓ MAPK, ↓ survivin,↓ XIAP, ↓ cIAP↑ Caspases

Cell Cycle Arrest↑ p53, ↑ p21, ↑ p27,↓ NF-B, ↓ MAPK,↑ cyclins A/B/D/E,↑ c-fos/c-jun, ↑ Myc,↑ beta catenin

Stress Response↓ DNA repair, ↓ Pgp,↑ TopII, ↑ TopI,↓ NF-B, ↓ MAPK,chemo- and radiosensitization

Accumulation of abnormal mutated /or misfolded proteins

Effects of Proteasome Inhibition on Tumor and Stromal Targets

Effects of Proteasome Inhibition on Tumor and Stromal Targets

Blockade of degradation of

- normal (short lived proteins) and

- abnormal proteins (more common in cancer cells)

cell death

Bortezomib: 1st in class approved in NHL – 1st activity shown in mantle cell

lymphoma

Bortezomib: 1st in class approved in NHL – 1st activity shown in mantle cell

lymphoma

1. O’Connor OA, et al. Br J Haematol. 2009;145:34-39. 2. Goy A, et al. J Clin Oncol. 2005;23:667-675. 3. Strauss SJ, et al. J Clin Oncol. 2006;13:2105-2112. 4. Belch A, et al. Ann Oncol. 2007;18:116-121. 5. Fisher RI, et al. J Clin Oncol. 2006;24:4867-4874.

Similar ORR across studies and for untreated / relapsed

1.5

mg

/m2

1.3

mg

/m2

Study N CR PR ORR, %

O’Connor[1] 40 5 (13) 14 (35) 47

Goy[2] 29 6 (20.5) 6 (20.5) 41

Strauss[3] 24 1 (4) 6 (25) 29

Belch, n[4] 13 untreated/ 15 relapsed

01

66

4647

PINNACLE, n (%)[5] 141 11 (8) 36 (26) 47 (33)

Total 262 24 (9) 74 (28) 98 (37)

Bortezomib: Summary of Efficacy in Mantle Cell Lymphoma

Bortezomib: Summary of Efficacy in Mantle Cell Lymphoma

Response / Subset Analysis

Median DOR in pts with CR/CRu not reached at 26.5 mos

Goy A, et al. Ann Oncol. 2009;20:520-525. Fisher RI, et al. J Clin Oncol. 2006;24:4867-4874.

Parameter Response Evaluable(n = 141)

Refractory MCL* (n = 58)

Prior High-Intensity Therapy†

(n = 58)

ORR, % 32 29 25

CR/CRu, % 8 6 10

Median DOR, mos 9.2 5.9 Not reached

Bortezomib: PINNACLE Trial Update Bortezomib: PINNACLE Trial Update

Most common adverse events (AEs, N=155)Most common adverse events (AEs, N=155)

Fisher RI et al. J Clin Oncol. 2006;24:4867-4874Gerecitano J et al. Br J Haematol. 2006;134(4):391-398

Frequent

Supportive care

Do not stop RX

Predictive response?

ORR 73% vs 33% w/o rash

ToxicityAny grade

n (%)Grade ≥ 3

n (%)

Fatigue 95 (61) 19 (12)

Peripheral neuropathies NEC

85 (55) 20 (13)

Constipation 77 (50) 4 (3)

Diarrhea NOS 73 (47) 11 (7)

Nausea 68 (44) 4 (3)

Rash NOS 43 (28) 4 (3)

Vomiting NOS 42 (27) 4 (3)

Anorexia 36 (23) 5 (3)

Dizziness (excluding vertigo)

36 (23) 5 (3)

Dyspnea NOS 35 (23) 7 (5)

Insomnia 33 (21) 1 (< 1)

Thrombocytopenia 33 (21) 17 (11)

MCL - Combination with chemo regimensMCL - Combination with chemo regimens

Furman et al, Cancer July 2010Ruan et al, JCO Feb 2011

Phase I R-CHOP

- Cornell – R-CHOP + BTZ days 1 & 4 / dose escalation 0.7, 1 and 1.3)

- 6 cycles / 20 pts 16 DLBCL – 4MCL

- Well tolerated / neuropathy (only 1gr 3) days 1 and 4 only ≠ GELA

- DLT not reached – dose established for phase II 1.3mg/m2

MCL - Combination with chemo regimensMCL - Combination with chemo regimens

Furman et al, Cancer July 2010Ruan et al, JCO Feb 2011

Phase I BTZ + R-CHOP

- Cornell – R-CHOP + BTZ days 1 & 4 / dose escalation 0.7, 1 and 1.3)

- 6 cycles / 20 pts 16 DLBCL – 4MCL

- Well tolerated / neuropathy (only 1gr 3) days 1 and 4 only ≠ GELA

- DLT not reached – dose established for phase II 1.3mg/m2

Med follow-up 30msMed PFS 21ms

Phase II BTZ + R-CHOP in MCL

Parameter Results

Nb pts 36

Med age 66y (45–80)

Stage 34 stage III-IV

MIPI 39% high MIPI

ORR 82%

CR-CRu 64%

Chang et al, BJH Aug 2011

CR,CRu,PR

Rituximab 375 mg/m2 d1

Cyclophosphamide300 mg/m2 q12h / d1-3

Doxorubicin50 mg/m2 48 h CI d1-2

Vincristine 2 mg d3

Dexamethasone40 mg d1-4

6 cycles

Rituximab375 mg/m2

qw × 4q6mo × 4

UntreatedMCL

(N= 30)

+ Bortezomib 1.5mg / m2 d 1 and 4 ONLY q 21d

excessive neuropathy changed to 1.3mg/m2

and vincristine to 1mg

Phase II study University of Wisconsin & Wisconsin Oncology Network – 30 pts

ORR 90% CR rate 77%

3-year PFS 63% and OS 86%

Modified R-HyperCVAD + BortezomibModified R-HyperCVAD + Bortezomib

76 pts eligible btw 5/07 - 10/08

Med age 62 (40-76)

91% stage III/IV

64 pts (84%) completed VcR-CVAD

B. S. Kahl et al, Blood, 2009 114: Abstract 1661

Response Value

ORR 96%

CR 75%

PR* 21%

MIPI 39% high MIPI

*6 PR no BM redone...

CR post modified R-HyperCVAD alone 64%Longer follow-up needed for PFS

Modified R-HyperCVAD + BortezomibECOG 1405

Modified R-HyperCVAD + BortezomibECOG 1405

Romaguera et al, Br Jnl Hematol Oct 2010

Dosing:

- cycles A days 1 and 4 @1.3mg/m2

- Cycles B: esc doses 0.7, 1, 1.3

No unexpected toxicity / one grade 3 sensory neuropathy

No pulmonary toxicity

19/20 CR (1 pt only ASCT)

Phase II ongoing

(Classic) R-HyperCVAD + Bortezomib(Classic) R-HyperCVAD + Bortezomib

MDACC and John Theurer Cancer Center

Combination Design Results / comments

SWOG

S0601

R-CHOP-Bz induction +

8 cycles maintenance Bz

Phase II completed

NCT 00376961

R-CHOP vs R-CHBzP Replacing vincristine with Bz Phase III ongoing

NCT00722137

MCL – Other Bortezomib CombinationsMCL – Other Bortezomib Combinations


SWOG

S0601



Phase II completed

NCT 00376961


NCT00722137

CALGB

C50403

HDT/ASCT

Maintenance Bz vs Consolidaton Bz

Randomized phase II maint vs consolidation



SWOG

S0601



Phase II completed

NCT 00376961


NCT00722137

CALGB

C50403

HDT/ASCT



NCI/WilsonBz R-EPOCH-Bz

Maintenance randomization

Window of opportunity markers / circulating MCL cells



SWOG

S0601



Phase II completed

NCT 00376961


NCT00722137

CALGB

C50403

HDT/ASCT



NCI/Wilson

(Grant ASCO 2011 #8022)

Bz R-EPOCH-Bz

Maintenance randomization

Window of opportunity markers / circulating MCL cells

Bendamustine + R + BTZ (Friedberg/ Blood March 2011)

Relapsed / ref indolent NHL

BR (benda 90mg.m2)

BTZ 1.3 days 1,4,8,11

29 pts 16FL, 7 MCL

ORR 93% / 71% in MCL

2y PFS 47%

CALGB BTZ + Len >10/19 pts resp / ongoing


O’Connor. Clin Lymphoma Myeloma. 2005;6:191; Leonard. Int J Cancer. 2006;119:971;

Demo. Cancer Res. 2007;67:6383; Ahn. Blood. 2007 Stewart. ASCO 2007 (abstr 8003);

Chauhan. Br J Cancer. 2006;95:961.

Marizomib (NPI-0052)Phase I

BortezomibApproved for MCL

Carfilzomib (PR-171)Phase II-III MM

Highly selective for chymotrypsin-like

Inhibits both chymotrypsin-like and

caspase-like

Binds all 3 enzymatic sites

Reversible Irreversible Irreversible

Other Proteasome InhibitorsOther Proteasome Inhibitors

0

% p

rote

asom

e in

hib

itio

n

D2 D8 D9D1

0

Time (weeks)

D15 D16

D1 D5

1 2 3 4

D14

D28

80

80

1 2

PX-171-001

QDx5; 9 day rest2 week cycle

Continuous suppression of proteasome activity

PX-171-002

QDx2 weekly for 3 wks; 12 day rest

4 week cyclePrevent full recovery of

proteasome between doses

O’Connor Clin Cancer Res Nov 2009Stewart ASCO 2007

ORR 54% in BTZ-naive patients and 26% in pts w/ prior exposure to bortezomibActivity in WM / NHL phase II P / Tox: hematological, NO or minimal neuropathy

CarfilzomibCarfilzomib

Annual “Celebrating Life and Liberty” Cancer Survivors Event JTCC - Sept 2011

Annual “Celebrating Life and Liberty” Cancer Survivors Event JTCC - Sept 2011

Lenalidomide mechanisms of action remains poorly understood /pleiotropic effects

Lenalidomide repairs suppressed T-cell immunological synapse formation in CLL and

follicular lymphoma

Antiangiogenic, microenvt, direct antiproliferative, NK, and T-regs

List A. N Engl J Med. 2007;357:2183-2186.Ramsay AG, et al. J Clin Invest. 2008;118: 2427-2437.

Lenalidomide / IMiDsLenalidomide / IMiDs

N = 203; MCL pts, n = 53

Median number prior Rx: 3 (1-8)

DOR: NR (13.7 mos in prior NHL-002 trial)

Results %

Response

ORR 41 14 pts prior bortezomib 57

CR/CRu 13

PR 28

SD 26

PD 33

Toxicity (myelotoxocity)*

Dose reductions 38

Zinzani PL, et al. ASH 2008. Abstract 262. Reeder CB, et al. ASH 2008. Abstract 1560. Czuczman MS, et al. ASH 2008. Abstract 268. Habermann TM, et al. Br J Haematol. 2009;145:344-349.

Lenalidomide in MCL – Trial 003Lenalidomide in MCL – Trial 003

NHL-003: MCL subset 54 pts

Zinzani et al. ASH # 262Reeder ASCO 2009, abst # 8569

Pat

ien

ts (

%)

PFS (days)

Kaplan-Meier Estimates (n=54)

100

80

40

20

0

60

0 100 200 300 400

Response Duration (days)

Kaplan-Meier Estimates (n=23)100

80

40

20

0

60

0 100 200 300 400

Median Response Duration has not been

reached

Res

po

nd

ers

(%)

Lenalidomide in MCL – Trial 003Lenalidomide in MCL – Trial 003

Study Results/Comments

MCL-001 “EMERGE”

Rel / ref MCL: single agent 25 mg/pivotal trial

117 / 135 pts enrolled

MCL-002 “SPRINT”

Randomized rel / ref MCL: lenalidomide vs invest’s choice

Zaja Ash 2010, abst # 966Ahmadi ASH 2010, abst # 3962

Lenalidomide in MCL – Next StepLenalidomide in MCL – Next Step

Study Results/Comments

Len + Rituximab

Len 20mg 21/28 days + R 375 mg /m2 x 4

46 pts (1-4 prior RX) / ORR 57% 33% CR

Median duration of response 18.9 ms

Gr 3-4 toxicities: neutropenia (17%), lymphopenia (7.2%), and thrombocytopenia (4.5%)

Len + Bortezomib CALGB / ongoing / target 54 pts

Len + Bortezomib + Rituximab

Sarah Cannon / ongoing

Wang ICML 2011Morrison, ASCO 2010 abst # 8106

Lenalidomide in MCL – Next StepLenalidomide in MCL – Next Step

Targeting PI3K/mTOR Pathway Targeting PI3K/mTOR Pathway

PI3K/mTOR pathway functions like

an “integrator” of cell stimuli

from the environment (cell surface

through number of receptor kinases)

and available “nutrients”

to allow cell survival / proliferation

PI3K and mTOR signaling critically regulates metabolism, growth or survival

Witzig T et al, Current Treat Oncol, July 2006

Targeting PI3K/mTOR Pathway Targeting PI3K/mTOR Pathway

Rapamycin extracted / Rapa Nui 70’s

Witzig T et al, J Clin Oncol 2005;23:5347-5356

Ansell S et al, Cancer 2008;113(3):508-14

• ORR 41% (11/27) 1 CR

• Median of 4 prior RX

• Better toxicity profile

25mg weekly - Med TTP 6.5 months - Med DOR 6.9 months

Similar ORR, DOR and TTP

@ both 250 mg and 25 mg

flat weekly dose

• 38% ORR (13/34) - 1 CR

• Grade 3 or 4 toxicity 91% pts

- Heme: thrombocytopenia (100%)

anemia (66%) neutropenia (77%)

- GI, mucositis, fatigue,

hyperglycemia, neuropathy

250mg weekly

Temsirolimus (CCI-779)

Temsirolimus – Phase III MCL Temsirolimus – Phase III MCL

Multicenter, open-label, phase III trial, International study

54 patients per arm; 2 -7 previous therapies

Temsirolimus treatment to continue until progression or unacceptable toxicity

Temsirolimus 175 mg qw x 3then 25 mg qw

RANDOMIZE

Relapsed/refractory MCL

Requiredrituximab

anthracyclinealkylating agent

(N = 162)Investigators’ choice

single agent

Temsirolimus 175 mg qw x 3then 75 mg qw

Hess, JCO, Aug 2009

Temsirolimus – Phase III MCL Temsirolimus – Phase III MCL

Multicenter, open-label, phase III trial

Hess, JCO, Aug 2009

Most common grade 3 or 4 AEs in the temsirolimus groups were thrombocytopenia, anemia, neutropenia and asthenia

Approved in EU

Witzig T et al, J Clin Oncol 2005;23:5347-5356Rizzieri DA et al, Clin Can Res 2008;14:2756-2762 Yee KW et al, Clin Cancer Res 2006;12:5165-5173

Drugior BTZ) Design Results/Comments


Temsirolimus + rituximab Relapsed MCL / > CR

Rituximab, Cladribine, and Temsirolimus

Other comb w/ R-CHOP/ BBR etc..

Reeder CB et al, ASH 2007, abstr 121 Hesse G et al, ASCO 2008, abstr 8513

mTOR Inhibitors – Next StepmTOR Inhibitors – Next Step







Everolimus (RAD001)

Oral 10 mg QD until PD or toxicity

MCL 19 cases

ORR: 32%; 11% CR, DOR 5.5 msWell tolerated: Gr 3-4 neutropenia 17% thrombocytopenia 35%

Same design for phase II pivotal trial (PILLAR-1) (prior BTZ)

International study completed









Everolimus (RAD001)

Oral 10 mg QD until PD or toxicity

MCL 19 cases

ORR: 32%; 11% CR, DOR 5.5 msWell tolerated: Gr 3-4 neutropenia 17% thrombocytopenia 35%

Same design for phase II pivotal trial (PILLAR-1) (prior BTZ)

International study completed

Next generation mTORi

CC223 OSI-027

(TORC1 and TORC2 inhibition) / ongoing



PI3K Delta Pathway DrivesProliferationCell survivalTrafficking

BCR

PI3KDelta

CD40

STAT

T308 S473AKT

JAKTRAF6

NF-Bpathway

JAK

mTOR

BTK

PLC2

PKC GSK-3

LYN

SYK LYN/SYK

T-cell Signalingstimulus

gp130 gp130

STAT BTK

PLC2

p70s6k elf4E

Malignant B-cell membrane

CXCR5BAFFR

Stromal cell

IL-6R

CXCL13BAFFIL-6

PI3K InhibitorsPI3K Inhibitors

Class IPI3K Isoform

Cell-Based Activity

PDGF-induced pAKT

LPA-induced pAKT

fMLP-induced CD63+

FcR1-induced CD63+

EC50 (nM) >20,000 1,900 3,000 8

Alpha Beta Gamma Delta

CAL-101

Selectivity relative to Class I PI3K isoforms involved in insulin signaling and other physiological functionsNo off-target activity against Class II or III PI3K, mTOR, or DNA-PKNo off-target activity seen in screen of >350 protein kinases (Ambit KINOMEscan™)

Reference: Lannutti, Blood 2010

CAL-101 is an Orally Bioavailable Small Molecule that Inhibits PI3K Delta

CAL-101 is an Orally Bioavailable Small Molecule that Inhibits PI3K Delta

NHL (N=51)

CharacteristicMCL

(N=21)iNHL

(N=30)CLL

(N=54)

Age, median[range], years

71 [52-82]

61.5[32-85]

62.5 [37-82]

Bulky disease, % 57 50 81

Adverse genetics (del 17p), % -- -- 36

Prior therapies, median [range], n

5 [1-12]

4[1-10]

5[2-15]

Prior therapy type, %

Rituximab 100 100 98

Alkylating agent 100 87 87

Anthracycline/anthracenedione 95 50 --

Purine analog -- 30 100

Bortezomib (MCL)/Alemtuzumab (CLL)

76 -- 31

Single-Agent CAL-101 in NHL and CLL Single-Agent CAL-101 in NHL and CLL

ORR: indolent NHL: 15/24 (62%) / MCL: 10/16 (62%) (mostly

PR) and 0/9 (0%) for DLBCL

Heavily pretreated: nb of prior therapies was 5 (1-12)

Median [range] duration of response in MCL: 3 months (1- 8)

Well tolerated / transient increase of LFTs

Increase / mobilization circulating B-cells / tumor cells


Best On-Treatment Change in Tumor Size(ITT Analysis)

-100

-75

-25

0

-50*

+25

+50

+75

+100

MCL(N=21)

iNHL(N=30)

CLL(N=54)

Inevaluable (patients without a follow-up tumor assessment)

* Criterion for response [Cheson 2007, Hallek 2008]

% C

hang

e in

Lym

ph N

ode

Area

MCL(n=21)

iNHL(n=30)

CLL (n=54)

Variety of dosings from 50 BID to 350 BID

Kahl, ASH 2010, abst # 17777O’Brien, Pan Pacific NHL Conf, Aug 2011


BCR-crosslinking activation series downstream tyrosine

kinases

BCR is critical for normal B-cell maturation and survival:

– transgenic mice / disruption of BCRs apoptosis mature B-

cells

In NHL BCR signal “chronically on” (w/o ligand) “tonic

signaling“ (prognostic value in DLBCL)

Chen, Blood 2008From: Nat Rev Immunol 2:945

Rationale for Targeting the BCR Pathway in Lymphoma

Rationale for Targeting the BCR Pathway in Lymphoma

Chen, Blood 2008Irish J M et al. PNAS 2010;107:12747-12754

Targeting the BCR Pathway in LymphomaTargeting the BCR Pathway in Lymphoma

BCR-associated kinases are targets of new drugs in preclinical and clinical development

Syk (spleen tyrosine kinase) inhibitors: R406, Portola’s Syk inhibitors1

Btk (Bruton’s tyrosine kinase) inhibitors: PCI-32765 from Pharmacyclics, Avila’s compounds (AVL-292)

1 Quiroga MP, et al. Blood 114(5):1029-37, 07/20092 Niedermeier M, et al. Blood 113(22):5549-57, 5/2009From: Nat Rev Immunol 2:945

Targeting the BCR Pathway in LymphomaTargeting the BCR Pathway in Lymphoma

• Bruton’s Tyrosine Kinase (Btk) is also an essential element of BCR signaling pathway / downstream of Syk

• Expressed in B-cells, mast cells and monocytes

• Mutations in Btk prevent B-cell maturation (400 mutations reported) clinically X-linked agammaglobulinemia

Bruton’s Tyrosine Kinase (Btk)A Critical B-Cell Signaling Kinase

Bruton’s Tyrosine Kinase (Btk)A Critical B-Cell Signaling Kinase

N

N

N

N

N H 2

O

N

O

PCI-32765

• Forms a specific and irreversible bond with cysteine-481 in Btk

• Potent Btk inhibition at IC50 = 0.5 nM

• Orally bioavailable with daily dosing resulting in 24-hr target inhibition qd

• Preclinically in CLL cells promotes apoptosis, inhibits ERK1/AKT phosphorylation, NF-κB DNA binding, cell proliferation AND cell migration and adhesion

Honigberg LA et al: Proc Natl Acad Sci U S A.107:13075, 2010Herman SEM et al: : Blood. 2011 Mar 21.

Ponader, et al., Proc ASH, 2010

PCI-32765: Novel Small Molecule Inhibitor of BTKPCI-32765: Novel Small Molecule Inhibitor of BTK

Median age, years (range)

M/ F, n (%)

65 (41-82)

38 (68) / 18 (32)

Histology, n (%) FL 16 (29)CLL/SLL 16 (29)MCL 9 (16)DLBCL 7 (16)MZL / MALT 4 (7)WM 4 (7)

Median prior therapies, number (range) 3 (1-10)

Fowler, Blood ASH 2010; 116: 964. Advani,ICML, Lugano 2011

Phase I NHL / CLL – Enrollment (56 pts)Phase I NHL / CLL – Enrollment (56 pts)

1 AEs >14%* Ecchymosis and pneumonia are combination of several preferred terms

Grade 3/4 Hematology2Most Common Adverse Events1

2 Based on clinical review of AE and Lab dataFowler, Blood ASH 2010; 116: 964. Advani, ICML, Lugano 2011

Phase I NHL / CLL - Adverse EventsPhase I NHL / CLL - Adverse Events

Pre-treatment

2 months on treatment

Absolute Lymphocyte Count

O’Brien, Pan Pacific NHL Conf, Aug 2011Burger, O‘Brien, ASH 2010, Blood 116: abst # 57

Pattern of Response: Blood Lymphocytes vs Lymph Nodes

Pattern of Response: Blood Lymphocytes vs Lymph Nodes

2 Based on clinical review of AE and Lab data

* 1 CLL pt had nodal response with lymphocytosis; ** Based on IgM

N CR PR SD PD NE

ORR%

ITT(n=56)

ORR%Eval

(n=50)

CLL/SLL

16 1 10 3* 2 69% 79%

MCL 9 3 4 1 1 78% 78%

WM 4 3** 1 75% 75%

FL 16 3 3 3 4 3 38% 46%

MZL/MALT

4 1 1 1 1 25% 33%

DLBCL 7 2 1 4 29% 29%

TOTAL

56 7 24 9 10 6 55% 62%

Fowler, Blood ASH 2010; 116: 964. Advani,ICML, Lugano 2011

Phase I – PCI-32765 – Best ResponsePhase I – PCI-32765 – Best Response

CLL/SLL

MCL

DLBCL

FL

Other Indolent NHL

% C

han

ge

of

Tu

mo

r B

urd

en

41/48 (85%) Fowler, Blood ASH 2010; 116: 964. Advani,ICML, Lugano 2011

PCI-32765 Max % Change in Tumor Burden

PCI-32765 Max % Change in Tumor Burden

Well tolerated with a modest toxicity profile

Majority of adverse events were Grade 1 or 2 in severity and easily managed/reversible

No cumulative toxicity with treatment duration > 6 months

Continuous occupancy of Btk at doses ≥ 2.5 mg/kg

Significant activity with durable responses observed in multiple histologic subtypes / MCL +++

Phase II trials ongoing and combinations

ConclusionsOral BTK inhibitor PCI-32765 in NHL

ConclusionsOral BTK inhibitor PCI-32765 in NHL

Other Targets in MCL Other Targets in MCL

Parek, Semin Cancer Biol. 2011

MULTIPLE new targets

(Non-cross) resistant with chemotherapy

CLINICAL TRIALS +++ / new combinations

BIOMARKERS? / to decide among novel therapies???

MCL - Novel Therapies - Conclusions MCL - Novel Therapies - Conclusions

Induction Consolidation Maintenance Relapse

CHOP/CVP/

MCP / Fludarabine

BEFORE

ASCT Debated??

No maintenance IFN ? HDT / ASCT

Dose-intensiveTherapies HD AraC

and Rituximab

NOW

HDT / ASCT Rituximab Bortezomib?

BTZ, CFZNew Mab

LenalidomidemTORiBTKiPI3Ki

Other: Bcl-2, HADCi

MCL: Considerable Progress!MCL: Considerable Progress!

Thank You!

jtcancercenter.org [email protected]

Thank You!

dr. goy mcl

Technology