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Steven M. Horwitz M.D. Associate Attending Memorial Sloan-Kettering Cancer Center

How do we best deploy novel agents for T cell lymphoma: What have we learned from key clinical trials and should they be employed upfront?. Steven M. Horwitz M.D. Associate Attending Memorial Sloan-Kettering Cancer Center Associate Professor Weill Cornell Medical College. 3 questions.

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Steven M. Horwitz M.D. Associate Attending Memorial Sloan-Kettering Cancer Center

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  1. How do we best deploy novel agents for T cell lymphoma: What have we learned from key clinical trials and should they be employed upfront? Steven M. Horwitz M.D. Associate Attending Memorial Sloan-Kettering Cancer Center Associate Professor Weill Cornell Medical College

  2. 3 questions How do we best deploy novel agents for T cell lymphoma? What have we learned from key clinical trials? Should they be employed upfront? Carefully and somewhat empirically Most ORR and toxicity Probably not routinely outside of clinical trial

  3. Single Agents in the Relapsed Setting

  4. Approved Agents in Relapsed/Refractory PTCL O’Connor OA, et al. J Clin Oncol. 2011;29:1182-1189 Coiffier B, et al. J Clin Oncol. 2012;30 :631-636 O’Connor OA, et al. ASCO 2013

  5. MLN8237 (Alisertib):Response (PR+CR) by Histology Barr et al. ASCO 2014

  6. Progression Free Survival: Relapsed/Refractory PTCL BCCA by PS Romidepsin N=130 Pralatrexate N=109 Belinostat N=129 Mak V et al. JCO 2013;31:1970-1976, O’Connor OA, et al. J Clin Oncol. 2011;29:1182-1189, Coiffier B, et al. J Clin Oncol. 2012;30 :631-636, O’Connor OA et al ASCO 2013

  7. Phase II Study of Pralatrexate 1.00 ORR 29% Median duration = 10.1 months 0.75 Permanently censored (eg, transplant) (n = 8) Continue in follow-up for response (n = 8) Proportion 0.50 0.25 0 0 3 6 9 12 15 18 Months O’Connor OA, et al JCO Jan 18 2011

  8. Continuous Therapy in Relapsed T-cell Lymphoma Belinostat DoR AITL Romidepsin PFS by Response Median 13.6 mos

  9. Pralatrexate for CTCL: Progression Free Survival Cohort >15 mg/m2 N=41 Med PFS 388 days

  10. Autologous Transplantation in Relapsed PTCL 1.0 0.8 0.6 % 0.4 0.2 0.0 0 12 24 36 48 60 72 84 96 108 120 132 PFS ICE months MSKCC The Stanford Experience Auto CIBMTR: PFS excluding pt in CR1 (Most patients ALCL) Median PFS 6 months Response to ICE 70% (28/40) Received ASCT 68% (27/40) • Benefits are unclear. Most single institution studies show low PFS rates while registry data suggests better outcomes Smith S, et al. JCO 2013. Abstract 689; Chen AI, et al. Biol Blood Marrow Transplant. 2008;14(7):741-747. Horwitz et al, ASH 2005 .

  11. Retrospective Analyses of Allogeneic Stem-cell Transplantation for PTCL French Registry N=77 TRM 34% MSKCC N=34 TRM 18% 5 year OS 57% 2 year OS 61% 5 year EFS 53% Le Gouill, S. et al. J Clin Oncol; 26:2264-2271 2008 Goldberg J. et al. Leuk Lymphoma. 2012 Jan 31

  12. Algorithmic Approach to Patients with Relapsed PTCL (NOS, AITL, ALCL) Allogeneic stem-cell transplantation Transplantation soon (Donor known; patient eligible) Combination chemotherapy (ICE, other combinations) Adequate response Donor known and eligible Transplantation unclear (Donor unknown; patient may or may not be eligible) Clinical trial or single agent No donor available Transplantation never (Physician or patient determines patient ineligible) Clinical trial or single agent POD intolerance Clinical trial or single agent Lunning et al. J Clin Oncol, 2013;31:

  13. Differential resposnesORR (%) by Lymphoma Subtype O’Connor OA, et al. J Clin Oncol. 2011;29:1182-1189. Coiffier B, et al. J Clin Oncol. 2012;30:631-636, Horwitz, S et al ICML 2013, Horwitz S M et al. Blood 2014;123:3095-3100 Pro B, et al. J Clin Oncol. 2012;30:2190-2196.

  14. Combinations

  15. DLBCL vs. PTCL OS 100 CHOP plus rituximab 80 60 Percentage of Treatment Group CHOP 40 PTCL 20 P < 0.007 0 0 0.5 1.0 1.5 2.0 2.5 3.0 Year after randomization Coiffier B et al. N Engl J Med. 2002;346:235-242. Vose et al. J Clin Oncol. 2008;26:4124–4130,

  16. T-cell Lymphoma: Current approaches that may be better than CHOP Nordic Study CHOEP-ASCT, N=166 5 yr OS 51% 1.0 International T-cell Project (retrospective) Anthracycline containing >85% N=299 5 yr OS 32% 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Better Results with more intensive therapy? Patient selection? Vose et al. J Clin Oncol. 2008;26:4124–4130, International T-cell Classification Project D’Amore, et al. J Clin Oncol. 2012;30(25):3093-3099

  17. Phase II Study of Denileukin Diftitox + CHOP in PTCL: “CONCEPT” Trial Interim Results • 7 D/C due to Adverse Events • anaphylaxis • pneumonia • pneumonitis • LFTs • cardiac arrest x 2 • TLS/rhabdo • POD-7 • Patient request • Early Discontinuation 20 (41%) • Phase II, newly diagnosed aggressive PTCL • 18mcg/kg/d D1-2, CHOP D3 • N=49 (80% PTCL/AITL/ALCL) • CR 75.7%, ORR 86.5% Foss et al. 10th ICML Lugano, June 5, 2008

  18. Alemtuzumab (A) + ChemotherapyFirst-line treatment of PTCL Single agent: N=14, Phase II, RR 36%, 5 deaths Enblad et al. Blood. 2004;103:2920-2924.

  19. The ACT trial AFTER the dose/age amendment R R A30- CHOP-14 A30 - CHOP-14 CHOP-14 CHOP-14 A30 - CHOP-14 CHOP-14 A30- CHOP-14 CHOP-14 CHOP-14 CHOP-14 A30 - CHOP-14 A30 - CHOP-14 CHOP-14 A30- CHOP-14 CHOP-14 A30 - CHOP-14 CHOP-14 CHOP-14 CHOP-14 CHOP-14 CHOP-14 HDT ACT-1 ACT-2 18 yrs 80 yrs 65 yrs CHOP-14 A60 A60 A60 CHOP-14 CHOP-14 A60 HDT No ALCL cases

  20. ACT-1 Response rates and time-related end-points 15 mo median follow-up Time-related end-points Response rates Primary Secondary EFS OS d’Amore et al, ASH 2012

  21. Phase I/II Pralatrexate in Combination with Gemcitabine The initial study design was to give pralatrexate day 1 and gemcitabine day 2 on a weekly schedule 3 out of every 4 weeks (Cohort A); due to hematologic toxicity observed the subsequent Cohorts received both drugs on Q2 week schedule (Cohort B – sequential days) and (Cohort C – same day pralatrexate followed 1h later by gemcitabine) Initial design: pralatrexate day 1 and gemcitabine day 2 weekly 3/4 weeks (Cohort A) Starting Doses Pralatrexate 15 mg/m2 and Gemcitabine 400 mg/m2 • Study modified to Every other Week dosing • Pralatrexate day 1 and gemcitabine day 2 (Cohort B) • Pralatrexate day 1 and gemcitabine 1 hour later (Cohort C) Horwitz et al ASH 2009 a1674

  22. CEOP-Pralatrexate PFS Cycle A: CEOP • Cyclophosphamide 750 mg/m2 IV d1 • Etoposide 100 mg/m2 IV d1-3 • Vincristine 2 mg IV day 1 • Prednisone 100 mg/day X 5 •Cycle B: Pralatrexate (P) - 30 mg/m2 IV d 15, 22 and 29 N=33 ORR 70% CR 52% months Advani et al. ASH 2013

  23. Romidepsin-CHOP Dose-escalation Phase New definition of DLTs (amendment °1) Cohort 6 12 mg/m2 N=3 Cohort 5 12 mg/m2 N=3 Cohort 4 10 mg/m2 N=3 Cohort 2 10 mg/m2 N=3 Cohort 1 10 mg/m2 N=3 Cohort 3 8 mg/m2 N=3 2 DLT Nausea DOSE USED FOR PHASE 2 1 DLT Pulmonary edema Gr 3 1 DLT Syncope Gr 3 2 DLTs Hem Gr 3 NO DLT NO DLT SAEs: 2-acute myocardial infarction 1-acute pulmonary edema, all after first cycle, none fatal Thrombocytopenia led to discontinuation of Romidepsin in 5 patients Dupuis et al. ICML 2013

  24. Romidepsin-CHOP PFS (Median Follow-up 10 months; n=27) CR 15/27 (55.6%) ORR 20/27 74% 1 year estimated PFS 63.9% (95%CI 35.4 – 82.5) Dupuis et al. ICML 2013

  25. Phase III Ro-CHOP Study International randomized, open-label study Principal objective: PFS improvement Planned accrual: 420 patients

  26. Brentuximab + CH-PResponse and PFS PFS N=26 Median F/U 21.4 mos Est 1 yr PFS 71% Fanale et al JCO epub September 2014

  27. A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in the Frontline Treatment of Patients with CD30-positive Mature T-cell Lymphomas BV + CH-P” x 6-8 cycles R A N D O M I Z E PTCL-CD30+ (> 10%) If ALK+ ALCL IPI >2 F/U Progression Death RESTAGE C4 Placebo+ CHOP” x 6-8 cycles N=300 Primary endpoint PFS approx. 45% improvement

  28. Phase III TrialsUntreated PTCL

  29. 3 questions How do we best deploy novel agents for T cell lymphoma? What have we learned from key clinical trials? Should they be employed upfront? Carefully and somewhat empirically Most ORR and toxicity Probably not routinely outside of clinical trial

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