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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 . - PowerPoint PPT Presentation
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Targeted therapy for Hodgkin’s Lymphoma
Larry W. Kwak, M.D., Ph.D.
Chairman, Department of Lymphoma/MyelomaJustin 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
00.2
0.40.6
0.81
1.2
1.41.6
1.82
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 tum
or c
hang
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
Bes
t % C
hang
e in
SP
D F
rom
Bas
elin
e(in
dex
lesi
ons
only
)
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
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
Brentuximab vedotin (SGN-35) ADCmonomethyl auristatin E (MMAE), microtubule disrupting agentprotease-cleavable linkeranti-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 ASCTDoses 0.1 to 3.6 mg/kg every 3 wksMTD 1.8 mg/kg86% tumor regression, 38% ORR, 24% CRPeripheral sensory neuropathy: ≥ grade 1 in 36%
• Weekly treatment44 pts (38 HL, 5 ALCL, 1 PTCL-NOS)68% prior ASCTDoses of 0.4 to 1.4 mg/kg on D1, 8, 15 of 28-day cycleMTD 1.2 mg/kg85% tumor regression, 58% ORR, 34% CRPeripheral 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=102Age* (years) 31 (1577)Gender (M / F) 48 / 54 ECOG status (0 / 1) 42 / 60Refractory 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, 20052 Gordon et al, presented at ASH 20103 Gallamini et al, 20074 Horning et al, 19945 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=26Cohort 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
AVD with brentuximab vedotin
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*
ABVD with brentuximab vedotin
N=25
AVD with brentuximab vedotin
N=26Neutropenia 20 (80) 20 (77)Anemia 5 (20) 3 (12)Febrile neutropenia 5 (20) 2 (8)Pulmonary toxicity 6 (24) 0Syncope 3 (12) 2 (8)Dyspnea 3 (12) 1 (4)Pulmonary embolism 3 (12) 0Fatigue 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
ABVD with brentuximab vedotin
N=25
AVD with brentuximab vedotin
N=26Any 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*
ABVD with brentuximab vedotin
N=25
AVD with brentuximab vedotin
N=26Any 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
ABVD with brentuximab vedotin
N=22
AVD with brentuximab vedotin
N=25Response 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 resultsHutchings et al. Blood 107:52-59, 2006.
Wedgwood et al. Submitted to ASH 2007.
FDG-PET positive16 Patients, prog=112-year PFS 0%
1.0
.08
.06
.04
.02
0.0Perc
ent P
rogr
essi
on-F
ree
PET neg61 Pts, 3 prog2 yr PFS 96%
3210
PET after 2 cycles
P < .001
Years
1.0
.08
.06
.04
.02
0.0Perc
ent P
rogr
essi
on-F
ree CR, PR
2 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%
Perc
ent E
vent
-Fre
e
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 IPS
Months
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 cmNEG PET: NO RT
6xBEACOPPesc6xBEACOPPesc 6xR-BEACOPPesc 2xBEACOPPesc