Targeted therapy for Hodgkin’s Lymphoma

Targeted therapy for Hodgkin’s Lymphoma

Larry W. Kwak, M.D., Ph.D.

Chairman, Department of Lymphoma/Myeloma

Justin Distinguished Chair in Leukemia Research

Co-Director, Center for Cancer Immunology Research

MD Anderson Cancer Center

Goals of Ongoing Research

• Improve remission rates and decrease risk of death

• Minimize side effects and maintain or prolong remissions

• Develop additional therapeutic options for relapsed/refractory disease (e.g. post-SCT)

STAT6 TARCJAK1/3

SOCS

Treg

Hodgkin’sReed-Sternberg cell

IL13

TH2

Vorinostat/SAHAMGCD0103

Bcl-xL

Survival

DCOX40L

TH

Che

mot

axix

of T

H2 c

ells

TH2

TH2

A

B

Development of (Deacetylase inhibitors) DACi in Hodgkin lymphoma

Dual antiproliferative activity: 1) Induction of cell cycle arrest and apoptosis (direct)2) Downregulation of TARC/CCL17 and alteration of the microenvironment (indirect)

Buglio et al, BLOOD 2008

Ligation of OX40 receptor (on T cells) inhibits the induction of Treg cells

C

Baseline31 year old femaleExtensive Prior TherapyRegimen Best ResponseABVD PRXRT Not EvalDHAP PRAuto Transplant Not EvalIGEV ProgressionDHAP ProgressionFludarabine/ Melphalan ProgressionAllo Transplant ProgressionDonor lymphocyte ProgressionMOPP Not EvalESHAP ProgressionIEV Progression

2 months

Oral HDAC Inhibitor Mocetinostat (MGCD0103) Clinical Activity in Hodgkin Lymphoma

PET

Younes et al, Lancet Oncology 2011

Single-arm Phase II study (n=51)

R21 “quick trials” grant

R2=0.40

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

0.00 0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80

Ratio of TARC change

Rat

io o

f tu

mo

r ch

ang

e DACi in Hodgkin lymphoma

Early decline in plasma TARC Levels correlates with clinical response

Younes et al, Lancet Oncology 2011

International oral Panobinostat (pan-HDACi) Phase II Study in HL

-100

-75

-50

-25

0

25

50

75

100

Be

st %

Ch

an

ge

in S

PD

F

rom

Ba

selin

e(i

nd

ex

lesi

on

s o

nly

)

Active

Discontinued

PR

PD

4 patients - SD (0%)

6 patients - off AE prior to Eval 11 patient - withdrew consent prior to Eval 11 patient - pending Eval 1 measurements

5 patients with SPD < 50% had new lesions at Eval 1

71% of patients with tumor reduction

Younes A, et al. JCO 2012

Efficacy of Unconjugated Anti-CD30 Antibodies in CD30 Positive Lymphomas

Drug Patients Dose Outcomes Authors

SGN-30 Chimeric Ab

24 pt (21 HL, 3 ALCL) Phase I

2 - 12 mg/kg weekly x 6

1 CR in cALCL, 6 SD (4 in HL)

Bartlett Blood 111: 2008

SGN-30 79 pt (38 HL, 41 sALCL) Phase II


HL No Resp, sALCL 17% Resp, 2 CR, 5 PR, All were ALK neg

Forero-Torres Br J Haematol, 2009

MDX-060 Fully Human Ab

72 pt (63 HL, 4 ALCL) Phase I/II


RR 8% (CRs in 2 HL, 2 ALCL)

Ansell JCO 25: 19, 2007

Brentuximab vedotin (SGN-35) ADCmonomethyl auristatin E (MMAE), microtubule disrupting agent

protease-cleavable linker

anti-CD30 monoclonal antibody

ADC binds to CD30

MMAE disruptsmicrotubule network

ADC-CD30 complex is internalized and traffics to lysosome

MMAE is released

Apoptosis

G2/M cellcycle arrest

Brentuximab Vedotin: Mechanism of Action

Brentuximab Vedotin: Phase I Results• Every 3 wk treatment

45 pts (42 HL, 2 ALCL, 1 AITCL)

73% prior ASCT

Doses 0.1 to 3.6 mg/kg every 3 wks

MTD 1.8 mg/kg

86% tumor regression, 38% ORR, 24% CR

Peripheral sensory neuropathy: ≥ grade 1 in 36%

• Weekly treatment44 pts (38 HL, 5 ALCL, 1 PTCL-NOS)

68% prior ASCT

Doses of 0.4 to 1.4 mg/kg on D1, 8, 15 of 28-day cycle

MTD 1.2 mg/kg

85% tumor regression, 58% ORR, 34% CR

Peripheral sensory neuropathy: ≥ grade 1 in 66%

Younes A et al, NEJM, 2010; Fanale, M et al, CCR, 2011

Maximum Reduction in Target Lesions

81% of patients achieved tumor reductions

Bartlett et al. JCO 27: 434s, 2009 (abst 8500).

Demographics and Baseline Characteristics in Pivotal HL Trial

N=102

Age* (years) 31 (1577)

Gender (M / F) 48 / 54

ECOG status (0 / 1) 42 / 60

Refractory to frontline therapy 72 (71%)

Refractory to most recent treatment 43 (42%)

Prior chemotherapy regimens* 3.5 (113)

Relapse ≤1 year post ASCT 72 (71%)

Time from ASCT to first post transplant relapse* 6.7 mo (0131)

* Median (range)

Younes , A et al, ICML, 2011

Conclusions from Pivotal HL Trial• Multiple durable CRs obtained with brentuximab vedotin

in highly treatment-refractory patients with HL

• Similar duration of remissions with or without allogeneic transplant

• Manageable adverse events; peripheral neuropathylargely reversible◦ 55% of patients had at least 1 event of peripheral neuropathy

◦ No grade 4 events of peripheral neuropathy

◦ Resolution or some improvement of PN : 80% at 13.2 weeks

CR ORR

Rate 34% 75%

Median Duration 20.5 mo 6.7 mo

Younes, A et al, ICML, 2011

Introduction of Targeted Therapies into Front-line

Rationale

• Treatment-naïve patients with Hodgkin lymphoma (HL) are commonly treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)1

• Frontline therapy with ABVD generally yields a 70% to 80% CR rate2,3

• Bleomycin-induced pulmonary toxicity occurs in 10% to 25% of patients receiving this regimen4

• Single-agent brentuximab vedotin (ADCETRIS®) in relapsed or refractory HL patients has shown an objective response rate of 75% (CR, 33%) with manageable toxicity5

1 Connors et al, 2005

2 Gordon et al, presented at ASH 2010

3 Gallamini et al, 2007

4 Horning et al, 1994

5 Smith et al, presented at EHA 2012

Study Design

• Phase 1, multicenter, dose-escalation study • Major eligibility criteria

◦ Treatment-naïve HL patients

◦ Age ≥18 to ≤60 years

◦ Stage IIA bulky disease or Stage IIB-IV disease

• Treatment design◦ 28-day cycles (up to 6 cycles) with dosing on Days 1 and 15

A(B)VD

Brentuximab Vedotin

Cycle 1 Cycle 2 Cycle 3

6 Cycles +/- XRT

Weeks0 2 4 6 8 10 12

Ansell S. et al. ASH 2012

Key Study Objectives

• To assess the safety profile of brentuximab vedotin in combination with ABVD and in combination with AVD

• To determine the maximum tolerated dose (MTD), if reached, of brentuximab vedotin in combination with ABVD and in combination with AVD

• To assess the antitumor activity of brentuximab vedotin in combination with ABVD and in combination with AVD

Description of Dose Cohorts

ABVD with brentuximab vedotin

N=25

AVD with brentuximab vedotin

N=26

Cohort 1 Cohort 2 Cohort 3 Cohort 4 Expansion

Brentuximab vedotin dose, mg/kg

0.6 0.9 1.2 1.2 1.2

Patients treated, N 6 13 6 6 20

Demographics and Baseline Characteristics

Parameter

ABVD withbrentuximab vedotin

N=25


N=26TotalN=51

Age, yearsa 35 (1959) 33 (1858) 33 (1859)

Gender 20 M / 5 F 17 M / 9 F 37 M / 14 F

IPS ≥4, n (%) 7 (28) 6 (23) 13 (25)

Bulky disease, n (%) 5 (20) 12 (46) 17 (33)

Stage, n (%)

IIA bulky 0 3 (12) 3 (6)

IIB 4 (16) 4 (15) 8 (16)

IIIA 5 (20) 3 (12) 8 (16)

IIIB 4 (16) 5 (19) 9 (18)

IV 12 (48) 11 (42) 23 (45)

a Median (range)

Summary of Adverse Events ≥Grade 3

Preferred term*


N=25


N=26

Neutropenia 20 (80) 20 (77)

Anemia 5 (20) 3 (12)

Febrile neutropenia 5 (20) 2 (8)

Pulmonary toxicity 6 (24) 0

Syncope 3 (12) 2 (8)

Dyspnea 3 (12) 1 (4)

Pulmonary embolism 3 (12) 0

Fatigue 1 (4) 1 (4)

Leukopenia 1 (4) 1 (4)

* Grade 3 or higher adverse events (AEs) occurring in more than 1 patient overall, regardless of relationship

Pulmonary Toxicity

Preferred term


N=25


N=26

Any event 11 (44) 0

Pulmonary toxicity 9 (36) 0

Interstitial lung disease 1 (4) 0

Pneumonitis 1 (4) 0

• Events generally occurred during Cycles 34• Two patient deaths were associated with pulmonary toxicity• Events resolved in 9 of 11 patients (82%)

◦ Median time to resolution was 2.6 weeks (range, 1.6 to 5 weeks)

• 8 of 11 patients with events discontinued bleomycin and were able to complete treatment with AVD combined with brentuximab vedotin

Peripheral Neuropathy

Preferred term*


N=25


N=26

Any event 18 (72) 20 (77)

Peripheral sensory neuropathy 18 (72) 19 (73)

Peripheral motor neuropathy 3 (12) 3 (12)

Muscular weakness 1 (4) 2 (8)

Paraesthesia 1 (4) 0* Summary of events using a standard MedDRA query (SMQ), regardless of relationship or severity

• Events were managed with dose modifications• Most events were Grade 1 or 2 and no events were Grade 4 or 5• One patient experienced Grade 3 events of peripheral sensory

neuropathy (fingers and toes) and peripheral motor neuropathy (hands and feet)

• Overall, 6 of 51 patients discontinued brentuximab vedotin due to peripheral neuropathy; these discontinuations occurred in Cycles 5 or 6

Maximum Dose and Dose-Limiting Toxicities

• Dose-limiting toxicities (DLTs) were defined as any Cycle1 toxicity requiring a dose delay ≥7 days in standard ABVD or AVD therapy

• No protocol-defined DLTs observed with either ABVD or AVD in combination with up to 1.2 mg/kg brentuximab vedotin (the maximum planned dose)

• A 1.2 mg/kg dose of brentuximab vedotin administered every 2 weeks is expected to achieve the same exposure (AUC) as the approved single-agent dose of 1.8 mg/kg every 3 weeks

Response Results at End of Frontline Therapy

Response per Investigatora


N=22


N=25

Response at end of frontline therapy, n (%)

Complete remission 21 (95) 24 (96)

Progressive disease 0 1 (4)

Not evaluable due to AEs 1b (5) 0

a Assessed using Cheson 2007b Patient had a Grade 5 event of pulmonary toxicity prior to the end of frontline therapy

• Response results at end of frontline therapy:

◦ ABVD cohorts: 21 of 22 CR (95%)

◦ AVD cohorts: 24 of 25 CR (96%)• In addition, 1 patient withdrew consent and 3 patients were lost to

follow-up prior to completion of frontline therapy and were not evaluable for response

Conclusions

• Concomitant administration of brentuximab vedotin and bleomycin is contraindicated due to pulmonary toxicity

• Recommended regimen is 1.2 mg/kg brentuximab vedotin every 2 weeks combined with AVD

• AVD combined with brentuximab vedotin appears to be well tolerated with manageable AEs

• CR rate of 96% observed at the end of frontline therapy with brentuximab vedotin combined with AVD

• Phase 3 study ongoing to assess treatment with brentuximab vedotin in combination with AVD as compared to ABVD alone in treatment-naive patients

Department of Lymphoma/Myeloma Disease –specific Working Groups

N. FowlerF. SamaniegoS. NeelapuL. FayadL. Kwak

T cell lymphoma

Multiplemyeloma

D. WeberJ. ShahS. ThomasM. WangR. AlexanianQ. Yi

Michael Wang, M.D.Nathan Fowler, M.D.

Co-DirectorsLymphoma Clinical Research

Robert Orlowski, M.D., Ph.D.Director

Myeloma Clinical Research

BurkittHIV

BrainTesticular

M. Fanale N. Fowler

M. FanaleN. FowlerJ. ShahJ. Westin

Larry W. Kwak, M.D., Ph.D.Chairman, Lymphoma/Myeloma

Low Grade lymphoma

Large Cell lymphoma

Mantle cell lymphoma

Hodgkins

L. FayadA. RodriguezF. HagemeisterJ. Westin

M. WangJ. RomagueraM. Fanale

F. Hage- meister

Phase I

Y. OkiM. Fanale

Rituximab plus ABVD

Rituximab weekly x 6 plus ABVD x 670 patients with stage II to IV diseaseMedian age 28 yoIPS ≥ 3 in 55%Protocol modified to include just IPS ≥ 3 based of initial results

Median f/u 32 months: EFS 85% & OS 98%78% of pts PET-2/3 negative5-year EFS for PET-negative vs positive of 93% vs 75%Improvement in EFS with R-ABVD compared to institutional ABVD outcomes

R-ABVD with IPS of 0-2 (89% vs 71%) and IPS ≥ 3 (80% vs 55%)

Copeland, A et al, ASH, 2010

R-ABVD for Advanced HL: Improvement in FFS Related to PET

Newer therapies are needed for HL with Pos PET Early pos PET after 2 ABVD predicts 100% relapseR-ABVD appears to give better results for high risk

patients with HLIn this prospective study, 55 patients with HL had a

PET after 2-3 R-ABVD: Therapy was not changed in these patients based on the PET findings

Results: PET Neg PET Pos p Patients (%) 43 (78) 12 (22) 5 Yr EFS 93% 75% 0.05

R-ABVD may be a better regimen than ABVD because PET positive patients have better results

Hutchings et al. Blood 107:52-59, 2006.Hutchings et al. Blood 107:52-59, 2006.

Wedgwood et al. Submitted to ASH 2007.Wedgwood et al. Submitted to ASH 2007.

FDG-PET positive16 Patients, prog=112-year PFS 0%

1.0

.08

.06

.04

.02

0.0Per

cen

t P

rog

ress

ion

-Fre

e

PET neg61 Pts, 3 prog2 yr PFS 96%

3210

PET after 2 cycles

P < .001

Years

1.0

.08

.06

.04

.02

0.0Per

cen

t P

rog

ress

ion

-Fre

e CR, PR2 Pts, 0 prog2 yr PFS 100%

3210

CT after 2 cycles

< PR62 Pts, 11 prog2 yr PFS 82%

P < .554

Years

PET vs CT for Stage I-IV HL: PFS Results by Radiographic Assessment after 2 CT Cycles

Hutchings et al. Blood 107:52-59, 2006

PET ps14 Pts, 11 prog2 yr PFS 0%

Per

cen

t E

ven

t-F

ree

100

75

50

25

04836240 6012

Months

EFS for R-ABVD

Score 0-1Score 0-2Score 2Score >2Score >3Score >4

R-ABVD for Advanced HD: EFS by IPS Score Compared with IPS Curves

Younes et al. Blood 106:431a, 2005 (abst 1499).

0 12 24 36 48 60 72 840

20

40

60

80

100

Score, 0Score, 1Score, 2Score, 3Score, 4Score, ≥5

EFS for IPSEFS for IPS

MonthsMonths

Hasencleaver and Diehl. NEJM 339: 1506-1514,1998.Hasencleaver and Diehl. NEJM 339: 1506-1514,1998.

GHSG HD18 Trial for Advanced HL: Study Design

2 x BEACOPP escalated

POS PET NEG PET

At End of Therapy:

POS PET: RT to Res Nodes >2.5 cm

NEG PET: NO RT

6xBEACOPPesc6xBEACOPPesc 6xR-BEACOPPesc 2xBEACOPPesc

Education

Targeted therapy for Hodgkin’s Lymphoma