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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.

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Presentation on theme: "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."— Presentation transcript:

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: Coiffier B, et al. J Clin Oncol. 2012;30 : O’Connor OA, et al. ASCO 2013 Belinostat N=129 OutcomesRomidepsin N=131 Pralatrexate N=109 2Median prior Rx 23 26%ORR25%29% 11% CR15%11% 15% PR11%18% 8.4Median duration of response 17 months10.1 months 1.6Median PFS4 months3.5 months

5 MLN8237 (Alisertib):Response (PR+CR) by Histology CategoryResponse n (%)* PTCL, NOS 4/13 (31%) Angioimmunoblastic 3/9 (33%) Anaplastic, ALK neg 1/2 (50%) Adult T-cell (HTLV-1) 1/4 (25%) Extranodal NK/T-cell 0/2 Transformed MF 0/7 Barr et al. ASCO 2014

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

7 Phase II Study of Pralatrexate Months Proportion ORR 29% Median duration = 10.1 months Permanently censored (eg, transplant) (n = 8) Continue in follow-up for response (n = 8) O’Connor OA, et al JCO Jan

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

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

10 Autologous Transplantation in Relapsed PTCL CIBMTR: PFS excluding pt in CR1 (Most patients ALCL) Smith S, et al. JCO Abstract 689; Chen AI, et al. Biol Blood Marrow Transplant. 2008;14(7): Horwitz et al, ASH The Stanford Experience Auto Benefits are unclear. Most single institution studies show low PFS rates while registry data suggests better outcomes PFS ICE months % MSKCC Median PFS 6 months Response to ICE 70% (28/40) Received ASCT 68% (27/40)

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

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

13 Differential resposnes ORR (%) by Lymphoma Subtype Subtype Pralatrexate Romidepsin Belinostat Brentuximab vedotin PTCL, NOS AITL ALCL O’Connor OA, et al. J Clin Oncol. 2011;29: Coiffier B, et al. J Clin Oncol. 2012;30: , Horwitz, S et al ICML 2013, Horwitz S M et al. Blood 2014;123: Pro B, et al. J Clin Oncol. 2012;30:

14 Combinations

15 DLBCL vs. PTCL Coiffier B et al. N Engl J Med. 2002;346: Vose et al. J Clin Oncol. 2008;26:4124–4130, OS Year after randomization P < CHOP plus rituximab CHOP Percentage of Treatment Group PTCL

16 T-cell Lymphoma: Current approaches that may be better than CHOP 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): International T-cell Project (retrospective) Anthracycline containing >85% N=299 5 yr OS 32% Nordic Study CHOEP-ASCT, N=166 5 yr OS 51% Better Results with more intensive therapy? Patient selection?

17 Phase II Study of Denileukin Diftitox + CHOP in PTCL: “CONCEPT” Trial Interim Results Foss et al. 10 th ICML Lugano, June 5, 2008  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% 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%)

18 Alemtuzumab (A) + Chemotherapy First-line treatment of PTCL CitationnPTCLA dose mg ChemoORR/CR% PFS/EFS % Toxicity Gallamani Blood CHOP-2875/71 (50% PTCL) 48 (2 yr)17% G4 infection Kim Chemother Pharmacol CHOP80/65 43 (1 yr)10% death infection Kluin- Nelemans Annals of Oncol, x3CHOP-1490/6027 (2 yr)15% EBV=LPD 20% TRM Single agent: N=14, Phase II, RR 36%, 5 deaths Enblad et al. Blood. 2004;103:

19 CHOP-14 HDT The ACT trial AFTER the dose/age amendment CHOP-14 A 30 - CHOP-14 HDT R R CHOP-14 A 30 - CHOP-14 CHOP-14 R R 18 yrs 65 yrs 80 yrs CHOP-14 A 60 CHOP-14 A 60 No ALCL cases ACT-1ACT-2

20 Time-related end-pointsResponse rates ACT-1 Response rates and time-related end-points Response ratesN (%) ORR42 (67) CR/CRu38 (61) PR4 (6) SD3 (5) PD16 (25) Not evaluable2 (3) Total63 (100) OS EFS PrimarySecondary End-point1-yr (95% CI) EFS55% (42-67) PFS54% (42-67) OS78% (67-88) 15 mo median follow-up d’Amore et al, ASH 2012

21 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) 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) Phase I/II Pralatrexate in Combination with Gemcitabine Phase I Initial Dosing CohortPDX/GemScheduleDLT 115/ 4003/4 weeks2/2Neutro: Gr3,4Throm: Gr3,4 10/4003/4 weeks2/2Throm: Gr /3003/4 weeks2/3Neutro: Gr 3, Throm: Gr3 Horwitz et al ASH 2009 a1674 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)

22 CEOP-Pralatrexate PFS N=33 ORR 70% CR 52% Advani et al. ASH 2013 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 months

23 Cohort 1 10 mg/m 2 N=3 Cohort 2 10 mg/m 2 N=3 Cohort 3 8 mg/m 2 N=3 Cohort 4 10 mg/m 2 N=3 Cohort 5 12 mg/m 2 N=3 1 DLT Syncope Gr 3 2 DLTs Hem Gr 3 NO DLT 1 DLT Pulmonary edema Gr 3 New definition of DLTs (amendment °1) Cohort 6 12 mg/m 2 N=3 2 DLT Nausea DOSE USED FOR PHASE 2 Romidepsin-CHOP Dose-escalation Phase 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 1 year estimated PFS 63.9% (95%CI 35.4 – 82.5) Romidepsin-CHOP PFS (Median Follow-up 10 months; n=27) CR 15/27 (55.6%) ORR 20/27 74% 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-P Response and PFS sALCLN (%)Other DxN (%)TotalN (%) ORR19 (100)7 (100)26 (100) CR16 (84)7 (100)23 (88) PR3 (16)--3 (12) Fanale et al JCO epub September 2014 PFS N=26 Median F/U 21.4 mos Est 1 yr PFS 71%

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 PTCL-CD30+ (> 10%) If ALK+ ALCL IPI >2 BV + CH-P” x 6-8 cycles Placebo+ CHOP” x 6-8 cycles RANDOMIZERANDOMIZE RESTAGE C4 F/U Progression Death N=300 Primary endpoint PFS approx. 45% improvement

28 Phase III Trials Untreated PTCL InterventionPatient Population Primary Endpoint s Status Alemtuzumab + CHOP14 + G-CSF vs CHOP14 + G-CSF Newly diagnosed PTCL EFSCompleted Brentuximab vedotin + CHP vs CHOPCD30+ PTCLPFSOngoing CHOP  pralatrexateNewly diagnosed PTCL PFS, OSClosed Romidepsin + CHOP vs CHOPNewly diagnosed PTCL PFSOngoing Belinostat + CHOP or Pralatrexate + CHOP vs CHOP Newly diagnosed PTCL PFSPlanned

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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