Targeted therapy for Hodgkin’s Lymphoma

251 views

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
251
On SlideShare
0
From Embeds
0
Number of Embeds
2
Actions
Shares
0
Downloads
11
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide
  • 3 current R trials: HD18 2 cycles of Be then if PET-2 positive adds R to Be to complete 8 cycles vs 8 Be and for PET-2 negative 4 vs 8 of Be; randomized R-ABVD vs ABVD, GITL stage I to II A 4 ABVD plus RT vs 4 RABVD
  • Targeted therapy for Hodgkin’s Lymphoma

    1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 10. Maximum Reduction in Target Lesions 81% of patients achieved tumor reductions Bartlett et al. JCO 27: 434s, 2009 (abst 8500).
    11. 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. 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. 13. Introduction of Targeted Therapies into Front-line
    14. 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. 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. 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. 17. Description of Dose Cohorts ABVD with brentuximab vedotin N=25
    18. 18. Demographics and Baseline Characteristics Parameter a Median (range)
    19. 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. 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. 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. 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. 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. 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. 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
    26. 26. 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
    27. 27. 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.
    28. 28. 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%
    29. 29. 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.
    30. 30. 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

    ×