1. 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

2. 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)

3. STAT6 TARCJAK1/3
SOCS
Treg
Hodgkin’s
Reed-Sternberg cell
IL13
TH2
Vorinostat/SAHA
MGCD0103
Bcl-xL
Survival
DC
OX40L
TH
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

4. Baseline
31 year old female
Extensive Prior Therapy
Regimen Best Response
ABVD PR
XRT Not Eval
DHAP PR
Auto Transplant Not Eval
IGEV Progression
DHAP Progression
Fludarabine/
Melphalan Progression
Allo Transplant Progression
Donor lymphocyte Progression
MOPP Not Eval
ESHAP Progression
IEV 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

5. 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
Ratiooftumorchange
DACi in Hodgkin lymphoma
Early decline in plasma TARC Levels
correlates with clinical response
Younes et al, Lancet Oncology 2011

6. International oral Panobinostat (pan-HDACi)
Phase II Study in HL
-100
-75
-50
-25
0
25
50
75
100
Best%ChangeinSPDFromBaseline
(indexlesionsonly)
Active
Discontinued
PR
PD
4 patients - SD (0%)
6 patients - off AE prior to Eval 1
1 patient - withdrew consent prior to Eval 1
1 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

7. 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
6 - 12
mg/kg
weekly x 6
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
1 - 15
mg/kg
weekly x 4
RR 8% (CRs in
2 HL, 2 ALCL)
Ansell JCO
25: 19, 2007

8. Brentuximab vedotin (SGN-35) ADC
monomethyl auristatin E (MMAE), microtubule disrupting agent
protease-cleavable linker
anti-CD30 monoclonal antibody
ADC binds to CD30
MMAE disrupts
microtubule network
ADC-CD30 complex
is internalized and
traffics to lysosome
MMAE is released
Apoptosis
G2/M cell
cycle arrest
Brentuximab Vedotin: Mechanism of Action

9. 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 treatment
44 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

10. Maximum Reduction in Target Lesions
81% of patients achieved
tumor reductions
Bartlett et al. JCO 27: 434s, 2009 (abst 8500).

11. Demographics and Baseline Characteristics
in Pivotal HL Trial
N=102
Age* (years) 31 (15 77)
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 (1 13)
Relapse ≤1 year post ASCT 72 (71%)
Time from ASCT to first post transplant relapse* 6.7 mo (0 131)
* Median (range)
Younes , A et al, ICML, 2011

12. 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 neuropathy
largely 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

13. Introduction of Targeted Therapies into
Front-line

14. 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

15. 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
Weeks
0 2 4 6 8 10 12
Ansell S. et al. ASH 2012

16. 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

17. Description of Dose Cohorts
ABVD with
brentuximab vedotin
N=25

18. Demographics and Baseline Characteristics
Parameter
a Median (range)

19. Summary of Adverse Events ≥Grade 3
Preferred term*
* Grade 3 or higher adverse events (AEs) occurring in more than 1 patient overall, regardless of relationship

20. Pulmonary Toxicity
Preferred term
• Events generally occurred during Cycles 3 4
• 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

21. Peripheral Neuropathy
Preferred term*
* 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

22. Maximum Dose and Dose-Limiting Toxicities
• Dose-limiting toxicities (DLTs) were defined as any Cycle
1 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

23. Response Results at End of Frontline Therapy
Response per Investigatora
a Assessed using Cheson 2007
b 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

24. 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

25. Department of Lymphoma/Myeloma Disease –
specific Working Groups
N. Fowler
F. Samaniego
S. Neelapu
L. Fayad
L. Kwak
T cell
lymphoma
Multiple
myeloma
D. Weber
J. Shah
S. Thomas
M. Wang
R. Alexanian
Q. Yi
Michael Wang, M.D.
Nathan Fowler, M.D.
Co-Directors
Lymphoma Clinical Research
Robert Orlowski, M.D., Ph.D.
Director
Myeloma Clinical Research
Burkitt
HIV
Brain
Testicular
M. Fanale N. Fowler
M. Fanale
N. Fowler
J. Shah
J. Westin
Larry W. Kwak, M.D., Ph.D.
Chairman, Lymphoma/Myeloma
Low Grade
lymphoma
Large Cell
lymphoma
Mantle cell
lymphoma
Hodgkins
L. Fayad
A. Rodriguez
F. Hagemeister
J. Westin
M. Wang
J. Romaguera M. Fanale
F. Hage-
meister
Phase
I
Y. Oki
M. Fanale

27. Rituximab plus ABVD
Rituximab weekly x 6 plus ABVD x 6
70 patients with stage II to IV disease
Median age 28 yo
IPS ≥ 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 negative
5-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

28. 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% relapse
R-ABVD appears to give better results for high risk
patients with HL
In 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.
Wedgwood et al. Submitted to ASH 2007.

29. FDG-PET positive
16 Patients, prog=11
2-year PFS 0%
1.0
.08
.06
.04
.02
0.0
PercentProgression-Free
PET neg
61 Pts, 3 prog
2 yr PFS 96%
3210
PET after 2 cycles
P < .001
Years
1.0
.08
.06
.04
.02
0.0PercentProgression-Free
CR, PR
2 Pts, 0 prog
2 yr PFS 100%
3210
CT after 2 cycles
< PR
62 Pts, 11 prog
2 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 ps
14 Pts, 11 prog
2 yr PFS 0%

30. PercentEvent-Free
100
75
50
25
0
4836240 6012
Months
EFS for R-ABVD
Score 0-1
Score 0-2
Score 2
Score >2
Score >3
Score >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 84
0
20
40
60
80
100
Score, 0
Score, 1
Score, 2
Score, 3
Score, 4
Score, ≥5
EFS for IPS
Months
Hasencleaver and Diehl. NEJM 339: 1506-1514,1998.

31. 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