MEETING EDUCAZIONALE: LINFOMI DI DERIVAZIONE T LINFOCITARIA

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1 MEETING EDUCAZIONALE: LINFOMI DI DERIVAZIONE T LINFOCITARIA PIER LUIGI ZINZANI Istituto di Ematologia e Oncologia Medica L. e A. Seràgnoli Università degli Studi di Bologna 43 Congresso Nazionale SIE Napoli 2011

2 DICHIARAZIONE Relatore: PIER LUIGI ZINZANI Come da nuova regolamentazione della Commissione Nazionale per la Formazione Continua del Ministero della Salute, è richiesta la trasparenza delle fonti di finanziamento e dei rapporti con soggetti portatori di interessi commerciali in campo sanitario. Posizione di dipendente in aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE) Consulenza ad aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE) Fondi per la ricerca da aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE) Partecipazione ad Advisory Board (CELGENE, MUNDIPHARMA, PFIZER, MILLENNIUM TAKEDA) Titolarietà di brevetti in compartecipazione ad aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE) Partecipazioni azionarie in aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE) Napoli, Mostra d Oltremare, ottobre 2011

3 NCCN Guidelines for Treatment of PTCL CHOP is the most commonly prescribed regimen in the first line se?ng 2,3 Suggested Treatment Regimens for PTCL (in alphabetical order) 1 First-line therapy Clinical trial preferred CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine First-line consolidation All patients except low-risk (aaipi) should be consolidated with highdose therapy and stem cell rescue (autologous) ALK-1 + ALCL is a subtype with good prognosis and does not need consolidative transplant if in remission 1. NaEonal Comprehensive Cancer Network. Clinical PracEce Guidelines in Oncology: Non Hodgkin s Lymphoma Available at hnp:// 2. Rosenstein LJ, Link BK. Clin Lymphoma Myeloma. 2008;8:S180 S Horwitz SM. Hematology Am Soc Hematol Educ Program. 2008;2008:

4 Improving on CHOP and CHOP based regimens Which pa(ents do well with CHOP and which need alterna(ve therapies? CHOP plus regimens Add etoposide Use targeted agents, such as alemtuzumab, denileukin di_itox, SGN 35, rituximab, etc. Add new agents (romidepsin, vorinostat) AlternaEves to CHOP type therapy ACVBP, + bortezomib Gemcitabine based regimens New doublets/triplets to bring to first line

5 CHOP, CHOEP, or Dose Dense CHOP? EFS, ALK+ ALCL EFS, younger patients Younger pts with good risk disease did better when etoposide was added to the regimen Schmitz et al, Blood 2010 EFS, other subtypes

6 CHOP Plus Alemtuzumab as First Line Treatment in PTCL GITIL Trial Histologically confirmed diagnosis of PTCL PTCL-NOS (14) AITL (6) ALK ALCL (3) EATCL (1) No uncontrolled infection (N=24) Korean Trial Newly diagnosed PTCL PTCL-NOS (10) Extranodal NK/T, nasal (3) AITL (3) ALK ALCL (2) SQ panniculitis-like TCL (2) ECOG PS 2 (N=20) GITIL=Gruppo Italiano Terapie Innovative nei Linfomi. 8-course CHOP plus Alemtuzumab (SQ); Day 2: 3 mg, Day 1: 10 mg, Day 0: 30 mg Then, 30 mg q28d for 1st 4 courses ONLY (N=4) 8-course CHOP chemotherapy, plus Alemtuzumab (SQ); Day 2: 3 mg, Day 1: 10 mg, Day 0: 30 mg Then, 30 mg q28d for all CHOP courses (N=20) CHOP chemotherapy, plus Alemtuzumab (IV) Day 1: 10 mg, Day 2: 20 mg Then, 30 mg day 1 q21d Gallamini. Blood. 2007;110:2316; Kim. Cancer Chemother Pharmacol. 2007;60:129.

7 Alemtuzumab + CHOP as First Line Treatment in PTCL: Results Trial ORR OS PFS 1 Yr 2 Yr 1 Yr 2 Yr GITIL 75% 70% 53% 54% 48% Korean 80% 44% n/a 43% n/a EFS- GITIL EFS-Korean Gallamini. Blood. 2007;110:2316; Kim. Cancer Chemother Pharmacol. 2007;60:129.

8 Alemtuzumab + CHOP toxicijes Toxicity Gallamini et al Grade 4 Infection-17% Sepsis, Aspergillosis, JC virus, PCP Kim et al Toxicity-Grade 3-4 Neutropenia 90%, Lymphopenia 95%, Febrile neutropenia 55% Infectious deaths 10% Study halted early due to SAE Decreased with sc administration and lower total dose Heterogeneity of CD52 expression PTCL 35-40% are positive* Varies by technique Flow vs Immunohistochemistry *Piccaluga et al Haematologica : , Rodig et al. Clin Cancer Res 2006;12:7174

9 CHOP plus Denileukin DiLitox, CONCEPT Phase II Trial PTCL histology Treatment-naïve except for prior radiation or single CHOP cycle ECOG PS 2 (N=49) Denileukin diftitox 18 µg/kg IV Days 1 and 2 CHOP Day 3 G-CSF support Day 4 Repeat q3w for up to 6 cycles MulEcenter, nonrandomized, open label study Primary objeceve: safety Secondary objeceve: ORR,CR, EFS G-CSF=granulocyte colony-stimulating factor. Foss. ASH (abstr 3449); National Institutes of Health website. Accessed 10/15/09.

10 Phase II Trial of Denileukin Di_itox + CHOP in PTCL 49 enrolled, 37 efficacy evaluable ORR: 86% in EE, 65% in ITT 73% CR in EE Median DOR 29.5 mo 2 year PFS: 41% 100% Progression-Free Survival All Eligible Patients with follow-up Registrations and Data as of May 5, % Overall Survival All Eligible Patients with follow-up Registrations and Data as of May 5, % 80% 60% 60% 40% 40% 20% 0% Total Failed / N 25 / Month Estimate 41% Months after Registration 20% 0% Total Deaths / N 15 / 49 Median in Months NR Months after Registration Foss. ASH (abstr 3449); Foss. Clin Adv Hematol Oncol. 2009;7(suppl 18):12.

11 CHOP plus Rituximab GELA Rituximab with CHOP for AITL 25 older pts (age 59 79) with newly diagnosed AITL treated with R CHOP pts completed 8 cycles 2 stopped for toxicity, 2 for PD ORR 80%, 44% CR 2 yr PFS 43%, OS 62% Conclusion: no be=er that CHOP alone

12 Other non CHOP regimens GELA ACVBP + Bortezomib 57 pts enrolled 46 pts completed 28 pts completed CR 45% CD46% CONCLUSION: not better than ACVBP alone Delmer et al, ASCO 2009

13 GEM P in Front Line and Relapsed PTCL Gem 1,000 mg/m 2 D1, 8, 15, cisplaen 100 mg/m 2 D15, methylprednisolone 1,000 mg D1 5 of each 28 day cycle N= 27; AITL (10), ALCL (6), PTCL(6), NK/T cell (3), ATLL(2), MF (1), and ETCL (1). Average cycles= 2.2 Response: 73% overall, 80% in first line 10/11 CR had stage III IV Grade III/IV neutropenia in 41% Kim et al, Royal Marsden Experience, ASCO 2010

14 Small-size phase III CHOP vs VIP-rABVD Simon A et al. BJH 2010, 151: Parameter Comment Values N pts N tot = 88 CHOP 21: 45 VIP rabvd: 43 Accrual period yrs (closed 8 yrs prior to publicaeon) Included subgroups Alk+ and Ann Arbor st.i II included Alk+: N=10 St I II: N=20 (11/9) Primary end point 2yr EFS CHOP 21: 41% VIP rabvd: 45%

15 Intensified induction + upfront ASCT in EATL Retrospective analysis of prospectively collected data Parameter Comment Values N pts Data period End points (historical comparison) CHOP like IfosfVepEpi + MTX+ASCT CHOP like IfosfVepEpi + MTX+ASCT 5 yr OS 5 yr PFS N tot = 54 N tot = vs 52% 22 vs 60%

16 Day Drug Level 1 Level 2 Level 3 Level 4 1 MTX (g/m 2 ) Ifosfamide (g/m 2 ) Dexamethasone (mg) VP16 (mg/m 2 ) every other day L asp (U/m 2 )

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18 FDA Approved Agents for Relapsed/Refractory PTCL Agent Regimen Total pts accrued ORR CR Response Duration Romidepsin (NCI) Romidepsin (pivotal) 14 mg/m2 weekly x 3 every 28 days 14 mg/m2 weekly x 3 every 28 days 43 38% 16% 8.3 mo % 16% 12 mo Pralatrexate (pivotal) 30 mg/m2 weekly x 6 of 7 weeks % 6% 9.4 mo Denileukin diftitox (MDACC)* 18 ug/kg daily x 5 every 21 days 27 50% 30% CD25+ 18% CD25-8 mo Brentuximab Vedotin (SGN- 35) 1.8 mg/kg IV every 21 days for 16 cycles % 57% 13.2 mo * Approved for CD25+ CTCL

19 And there are so many new drugs or at least drugs new to PTCL CD 52 alemtuzumab IL2 R Denileukin Di_itox PentostaEn L Asparaginase Nelarabine Clofarabine Vorinostat Bortezomib Lenalidomide Temsirolimus CSA Sorafenib Pralatrexate Depsipeptide Everolimus Syk inhibitors Enzastaurin Anti-CD 4 Anti-CD 2 Anti-CD 30 -naked or conjugated Chemokine receptors Fodosine Plitidepsin Others

20 PROPEL: A MulE center Phase 2 Open label Study of Pralatrexate with Vitamin B 12 and Folic Acid SupplementaEon in PaEents with Relapsed or Refractory Peripheral T cell Lymphoma (PTCL) PDX 30 mg/m 2 once weekly IV push 6 weeks Vitamin B 12 1 mg IM q 8-10 weeks Folic acid mg PO QD Cycle 1 Cycle 2 Cycle 3 Cycle 4 Weeks Response assessment Response assessment Treat until progression or intolerance O Connor OA, et al JCO Jan

21 PROPEL Summary of Response by Central Review: IWC a Best response n (%) n = % CI CR + CRu + PR 29 (27) (19%, 36%) CR 7 (6) CRu 2 (2) PR 20 (18) SD 24 (22) PD 40 (37) UE 2 (2) ND 14 (13) O Connor OA, et al JCO Jan

22 Time to response 63% of responders did so at Cycle 1 37% of responses occurred between cycle 2 and 7 % of responders Cycle Number First Response (IWC) Median Jme to response (IWC) Days (range) First response 45 (37 349) Best response 96 (37 483) Data on File, Mundipharma InternaEonal Ltd

23 PROPEL: PFS with pralatrexate vs PFS with earlier lines of therapy O Connor et al, EHA 2011, Poster 0363

24 Final Results From a Pivotal, Multicenter, International, Open-Label, Phase 2 Study of Romidepsin in Progressive or Relapsed Peripheral T-Cell Lymphoma Following Prior Systemic Therapy Bertrand Coiffier, 1 Barbara Pro, 2 H. Miles Prince, 3 Francine Foss, 4 Lubomir Sokol, 5 Matthew Greenwood, 6 Dolores Caballero, 7 Peter Borchmann, 8 Franck Morschhauser, 9 Martin Wilhelm, 10 Lauren Pinter-Brown, 11 Swaminathan Padmanabhan, 12 Andrei Shustov, 13 Jean Nichols, 14 Susan Carroll, 14 John Balser, 15 Steven Horwitz 16 1 Hospices Civils de Lyon, Lyon, France; 2 Fox Chase Cancer Center, Philadelphia, PA; 3 Peter MacCallum Cancer Centre, East Melbourne, Australia; 4 Yale Cancer Center, New Haven, CT; 5 Moffitt Cancer Center, Tampa, FL; 6 Royal North Shore Hospital, Sydney, Australia; 7 Hospital Universitario de Salamanca, Spain; 8 Klinikum der Universität zu Köln, Germany; 9 Hôpital Claude Huriez, de Lille, France; 10 Klinikum Nürnberg Nord, Nürnberg, Germany; 11 UCLA Medical Center, Los Angeles, CA; 12 The University of Texas Health Science Center at San Antonio, San Antonio, TX; 13 University of Washington, Seattle, WA; 14 Celgene Corporation, Cambridge, MA; 15 Veristat, Inc., Centre Hospitalier Universitaire Holliston, MA; 16 Memorial Sloan-Kettering Cancer Center, New York, NY

25 Study Schema Romidepsin 14 mg/m 2 (4 hour IV) on days 1, 8, and 15 of a 28-day cycle x 6 cycles Responding patients could continue to receive treatment beyond 6 cycles at discretion of patient and investigator Response was assessed every 2 cycles with follow-up every 2-3 cycles

26 Overall Response Rates Best Response Category IRC (N = 130) n (%) InvesJgators (N = 130) n (%) ObjecEve response (CR/CRu + PR) 34 (26) 38 (29) Complete response (CR/CRu) 17 (13) 21 (16) CR 10 (8) 18 (14) CRu 7 (5) 3 (2) ParEal response (PR) 17 (13) 17 (13) Stable disease (SD) 32 (25) 22 (17) Progressive disease (PD)/not evaluable a 64 (49) 70 (54) a Insufficient efficacy data to determine response due to early terminaeon for 22 paeents in IRC assessment and 11 paeents in InvesEgators assessment; included as non responders in the analysis.

27 DuraJon of Response Survival distribution function (%) CR/CRu + PR (IRC) CR/CRu (IRC) Duration (days)

28 Gemcitabine in PTCL Study Regimen N ORR Sallah et al Br J Haematol Zinzani et al Phase II Ann Oncol Royal Marsden Phase II Arkenau. Haematologica 2007 Spencer et al Pilot study Intern Med J Kim et al Pilot study Cancer Chemother Pharmacol Gemcitabine monotherapy 10 60% Gemcitabine monotherapy 39 69% GEM P 16 69% VGF 10 70% CHOP EG 26 77% CHOP-EG=CHOP-etoposide, gemcitabine; GEM-P=gemcitabine, cisplatin, methylprednisolone; VGF=vinorelbine, gemcitabine, filgrastim. Courtesy dr. Advani (adapted)

29 Gemcitabine monotherapy Period Duration of response: mo

30 Table 1. Patients and tumor characteristics Arkenau, H.-T. et al. Haematologica 2007;92: GEM-P (Gemcitabine, Cisplatin, Methylprednisolone) in R/R PTCL ORR 69 % with CR 19 %

31 Studies of Alemtuzumab in PTCL Study Disease Pt No Treatment Regimen ORR CR Response durajon (months) Median OS (range) months Enblad Refractory PTCL 14 Alemtuzumab 36% 21% 2, 6, 12 Zinzani Relapsed PTCL 6 Alemtuzumab (low dose) 60% 33% Gallamini PTCL (untreated) 24 CHOP + Alemtuzumab 75% 71% 53% Kim PTCL (untreated) 16 CHOP + Alemtuzumab 80% 65% 43% Weidmann PTCL naïve FCD + Alemtuzumab 61% (63%) 39% PFS 11.8 months 25.9

32 Anti CD4: Zanolimumab Humanised antibody 21 patients with CD4+ relapsed/refractory PTCL (no CTCL) 9 AITL, 7 PTCL-NOS, 4 ALCL, 1EATL 980mg IV weekly x 12 weeks Medain age 69 years 17 stage III/IV ORR 24% (2CRu) Acceptable safety profile D Amore et al. Brit J Haem 2010; 150:

33 AnJ CCR4 (KW 0761) Defucosylated humanised anebody CCR4 expressed on ATL, PTCL, CTCL Phase I ORR 31% 1 Phase II relapsed ATL 2 27 relapsed paeents (14 acute, 6 lymphoma, 7 chronic) ORR 50%; 8CRs AEs 33% neutropenia, 50% skin rash Phase I/II relapsed CTCL 3 38 paeents (23 MF, 15SS) ORR 38% (47% SS) 2 CRs 1 Yamamoto et al, J Clin Oncol 2010; 2 Ishida et al, ASH 2010 abstract 285; 3 Duvic et al, ASH 2010 abstract 962

34 CD30 transmembrane receptor restricted to acevated lymphocytes SGN 35 CD30 targeted anebody (cac10) conjugated to monomethyl auristaen E (MMAE), an ane tubulin agent SelecEvely induces apoptosis in HL and ALCL cells: Binds to CD30 Becomes internalized Releases MMAE Immuno Conjugates AnJ CD 30: SGN 35 SGN-35 Antibody -Drug Conjugate SGN-35 binds CD30 Endocytosis CD30 ADC traffics to lysosome Enzymatic linker cleavage releases MMAE from ADC MMAE binds tubulin G2/M cell cycle arrest & apoptosis

35 Brentuximab VedoJn (SGN 35) Phase II mulecentre study 58 Relapsed/ Refractory systemic ALCL 1.8mg/kg q 3 weeks Iv for up to 16 cycles Median age 52y (14 76) 72% ALK neg Median prior therapy 2 (1 6), 26% ASCT ORR 86% (53% CR), remainder SD (97% tumour reduceon) Cutaneous lesions 93% CR 14 paeents proceeded to SCT Nausea, diarrhoea, peripheral neuropathy, neutropenia Shustov et al, ASH 2010, abstract 961

36 Phase II Clinical Trial of Belinostat (PXD101) in PaJents with Recurrent or Refractory CTCL or PTCL Diagnosis Study Objectives -Response rate -Safety CTCL Belinostat 2 cycles PTCL Patient Population CTCL or PTCL Failed 1 prior line of therapy Response Assessment Dosing Belinostat 1000 mg/m 2 administered as a 30 min IV infusion once daily on days 1-5 every 3 weeks CR, PR, SD Belinostat Up to 6 more cycles or PD Terminate study treatment Two-Stage Design (by study arm/diagnosis): terminate study arm if 1/13 pts show response; if 2/13 show response continue enrollment Simon optimal two-stage design to test null hypothesis that the true success proportion is at most 10% PD

37 PTCL: Exposure & Efficacy Median Cycles=3 (1 8) ORR in 17 Evaluable PaJents = 24% 3 CR (PTCLu IB, IIIA and IIIB) 1 PR (AITL IVB) 4 SD (ALCL IIA,IIB, PTCLu IVB, NK/T IVA) CharacterisJc Time to ObjecHve Response (days), n=4 Median Range Time to Complete Response (days), n=3 Median Range DuraHon of ObjecHve Response (days), n=4 Median (3 ongoing) Range Progression Free Survival (days), n=19 Median (7 pts without event) Range Result

38 Other New Drugs Lenalidomide Phase II, 25 mg D1 21/28 cycle 8/24 pts responded ongoing phase II (Dueck, Cancer 2010) 3/10 pts responded phase II (3 CR) (Zinzani, Leukemia Lymphoma 2011) RAD001 (6 MF, 6 PTCLU) 10 mg daily (4 week cycles) ORR 42 % (5/12 PR and 2/12 SD); 3 PR in 6 PTCLU

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40 The ACT trials Original design R R A 60 - A 60 - A 60 - A 60 - A 60 - A 60 - A 60 - A 60 - A 60 - A 60 - A 60 - A 60 - Auto Auto

41 ACT-1 amendment R 60 A - A - A - A - 1) Max age: 60 yrs 2) ALCL: excluded regardless of alk-status (NLG-T-01 results) 3) ALZ dose reduction: from 60 mg pr course to 30 mg pr course (course 1-4), no antibody in course 5 and 6 (two last courses prior to ASCT) Auto Auto

42 The ACT trial NLG-T-02 DSHNHL B 18 R 60 R 80 A 30 - A 30 - A 30 - A 30 - A 30 - A 30 - A 30 - A 30 - Auto Auto Accrual pr. June 2011: 128 pts (ACT-1: 70 ; ACT-2: 58)

43 A PHASE IB/II STUDY OF ESCALATING DOSES OF ROMIDEPSIN IN ASSOCIATION WITH CHOP (Ro CHOP) IN THE TREATMENT OF T CELL LYMPHOMAS PaJents: PTCL all types (except HTLV 1 related, CTCL, Alk+) CHOP 21 + increasing dose levels of Romidepsin x 8 cycles 1. ObjecJve: assess feasibility of combinajon and recommended dose (RD) 2. ObjecJve: Assess safety and efficacy (ORR, PFS) AcJvely enrolling 43

44 Randomized study with Ro CHOP in PTCL In planning start once RD in phase 1 obtained R 8 cycles of CHOP every 3 weeks 8 cycles of Ro CHOP every 3 weeks PaEents Previously untreated paeents With any subtype of PTCL Stage I to IV years old No contra indicaeon to CHOP Primary endpoint: Progression free survival Secondary endpoints: OS, DFS, safety

45 Proposed trials -Pralatrexate as a Maintenance Therapy after CHOP in PTCL In US: CEOP alternating with PDX for 3 weeks in untreated patients

46 Phase III Study: Denileukin Diftitox(E7777) with CHOP or CHOP alone in newly diagnosed PTCL Treatment Group A CHOP-21 Lead-in to establish dose of E7777 with CHOP Doses= 3-18 ug/kg 20 pts 332 pts E7777 days 1,2 CHOP-21 E7777 is a different formulation of denileukin diftitox which may have different potency Primary endpoint: PFS Secondary endpoints: ORR, DOR, survival at 3 years, # pts eligible for transplant who receive transplant

47 Phase 1 SGN-35 FL ALCL study* A Phase 1 Study of Brentuximab Vedotin (SGN- 35) Administered Sequentially with CHOP and Concurrently with CH-P as Front-Line Therapy in Patients with Systemic ALCL Population: ALK-negative any IPI score and ALK-positive IPI 2 Primary Objectives: Safety Secondary Objectives: Activity, PK Understand BV safety in sequence and in combo with CHOP/CH-P Arm 1, N=20 SGN-35 x 2 cycles CHOP x 6 cycles SGN-35 x 8 cycles Arm 2, N=12-18 CH-P x 6 cycles + SGN or 1.8 mg/kg SGN-35 x 10 cycles *Proposed amendment #1

48 PTCL: Getting Beyond CHOP CHOP will not cure most patients with PTCL? Transplantation may consolidate remissions But we still need more effective initial therapies New combinations and combinations of new agents Gemcitabine+bortezomib 2005 Phase I Results of Combination Gemcitabine and Bortezomib for Relapsed/Refractory Nodal T-NHL and Aggressive B-NHL Pralatrexate +Bortezomib Pralatrexate Compliments the Activity of the Proteasome Inhibitor Bortezomib in in Vitro Models of Lymphoid T-Cell Malignancies Pralatrexate+Gemcitabine 1570 A Phase 1/2A Open-Label Study of Pralatrexate and Gemcitabine in Patients with Relapsed or Refractory lymphoproliferative Pralatrexate+Romidepsin Phase I-II, NY University (Zain, O Connor)