Nuove opportunità di cura. Stefano Sacchi, Modena

Transcription

1 Nuove opportunità di cura Stefano Sacchi, Modena

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3 Antiangiogenesis therapies The goal is to target the blood supply that feeds tumors. Vorinostat (suberoylanilide hydroxamic acid - SAHA) TOPIC SEARCH: Mechanisms PubMed Outcome ASCO Medscape PubMed Safety ASCO PubMed More agents of this type...

4 Bevacizumab (anti-vegf) TOPIC SEARCH: Mechanisms PubMed Outcome ASCO Medscape PubMed Safety ASCO PubMed Cilengitide (EMD ) TOPIC SEARCH: Mechanisms PubMed Outcome ASCO Medscape PubMed Safety ASCO PubMed CC-513 (Lenalidomide/ Revlimid) TOPIC SEARCH: Mechanisms PubMed Outcome ASCO Medscape PubMed Safety ASCO PubMed FR91228 TOPIC SEARCH: Mechanisms PubMed Outcome ASCO Medscape PubMed Safety ASCO PubMed MS-275 TOPIC SEARCH: Mechanisms PubMed Outcome ASCO Medscape PubMed Safety ASCO PubMed Sorafenib (BAY 43-96) TOPIC SEARCH: Mechanisms PubMed Outcome ASCO Medscape PubMed Safety ASCO PubMed Thalidomide TOPIC SEARCH: Mechanisms PubMed Outcome ASCO Medscape PubMed Safety ASCO PubMed

5 1 Completed Avastin Plus Rituximab for Patients With B -Cell Non-Hodgkin's Lymphoma 2 Recruiting A Study of Avastin (Bevacizumab) in Combination With MabThera (Rituximab) and CHOP Chemotherapy in Patients With Diffuse Large B -Cell Lymphoma. 3 Active, not recruiting Bevacizumab in Treating Patients With Non -Hodgkin's Lymphoma 4 Recruiting A Study of Rituximab and Bevacizumab in Patients With Follicular Non - Hodgkin's Lymphoma 5 Recruiting Bevacizumab and AZD2171 in Treating Patients With Metasta Solid Tumor or Lymphoma tic or Unresectable 6 Completed Bortezom ib and Antiviral Therapy Followed By Effusion Drainage, Bevacizumab, and Combination Chemotherapy in Treating Patients With Primary Effusion Lymphoma 7 Recruiting Bevacizumab + CHOP -Rituximab in Untreated Mantle Cell Lymphoma 8 Recruiting Bevacizumab and Combination Chemotherapy in Treating Patients With Peripheral T -Cell Lymphoma or Natural Killer Cell Neoplasms 9 Recruiting Combination Chemotherapy, Rituximab, and Bevacizumab in Treating Olde r Patients With Stage II, Stage III, or Stage IV Diffuse Large B -Cell Lymphoma 1 Active, not recruiting Study of CGC When Used in Individual Combinations With 1) Gemcitabine or 2) Docetaxel or 3) Bevacizumab or 4) Erlotinib or 5) Cisplatin or 6) 5 - Flurouracil or 7) Sunitinib in Patients With Advanced Solid Tumo rs or Lymphoma

6 Lenalidomide in Indolent Non Hodgkin Lymphoma Update June 28

7 Phase II trial of Len monotherapy in RR Indolent NHL Demographics Pts(#) Median age Male Median time from diagnosis Median no. of prior therapies Prior antracyclines & alkylating agents & alkaloids & rituximab At least 2 of the above % 4.4 yrs 3 42% 77% Ann Arbor stage at enrollment I 1 (2 %) II 11 (26%) III 7 (16 %) IV 24 (56%) Wiernik et al; EHA 28

8 Response Rate by Histology Histology Indolent NHL 43 (1%) Response Rate according to Histology CR CRu PR OR 2 (5%) 1 (2%) 7 (16%) 1 (23%) Follicular center lymphoma grade 1/2 22 (51 %) 2 (9%) 4 (18%) 6 (27%) Smally lymphocytic lymphoma 18 (42 %) 1 (6%) 3 (17%) 4 (22%) Nodal marginal zone B cell lymphoma 2 (5 %) Extra nodal marginal zone B-Cell lymphoma of MALT type 1 (2%) Wiernik et al; EHA 28

9 Median duration of Response for all patients Wiernik et al; EHA 28

10 Grade 3/4 adverse events Neutropenia Thrombocytopenia Anemia Leukopenia Asthenia Pneumonia Lymph node pain Pancytopenia Pyrexia Grade 3 13 (3%) 6 (14%) 3 (7%) 4 (9%) 2 (5%) 2 (5%) Grade 4 7 (16%) 2 (5%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) Wiernik et al; EHA 28

11 SLL subgroup analysis Demographics Pts(#) Median age Male Median time from diagnosis % 4.1 yrs Ann Arbor Stage I 1 (6 %) II 3 (17%) III 3(17 %) Median no. of prior therapies 3 IV 11(61 %) Refractory to last therapy 63% Prior antracyclines & alkylating agents & alkaloids & rituximab 28% At least 2 of the above 94% Presence of extranodal sites 61% Witzig et al; ASCO 28

12 SLL subgroup analysis: Response date OR CRu PR Stable Disease Progressive disease No response assessment No. (%) 4 (22%) 1(6%) 3(17%) 7 (39%) 2 (11%) 5 (28%) Witzig et al; ASCO 28

13 SLL subgroup analysis: Duration of Response Median duration of Response: > 14.3 months Witzig et al; ASCO 28

14 SLL subgroup analysis: PFS Estimated median PFS: 6.9 months Witzig et al; ASCO 28

15 SLL subgroup analysis: Safety data Neutropenia Thrombocytopenia Anemia Leukopenia Pneumonia Lymph node pain Pancytopenia Pyrexia Grade 3 7 (39%) 11 (17%) 2 (11%) 2(11%) 2 (11%) Grade 4 6(33%) 2 (11%) 1(6%) 1 (6%) 1 (6%) 1 (6%) 3 pts. with lesions >5cm had Grade 1/2 tumor flare reactions Witzig et al; ASCO 28

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17 Lenalidomide plus Rituximab Rituximab and lenalidomide, as single agents, have antilymphoma activity in vivo and in vitro. Pattern of side effects is different and not overlapping. The cytotoxic effect of Rituximab appears to involve CDC, ADCC and induction of apoptosis. Recent data suggest that the modulation of immunoeffector cells by lenalidomide can enhance the antitumor activity of rituximab and partially overcome the rituximab resistance in cell lines of relapsed/refractory NHL. Lenalidomide appears in fact to greatly enhance the monocyte and NK-mediated ADCC exerted by rituximab, resulting in an increase of cancer cell killing compared to the single drugs

18 Clinical Protocol Phase II study of lenalidomide in combination with rituximab (R) for the treatment of indolent non follicular non Hodgkin lymphoma (NHL ). Study ID: INFL8 Eudract Number: Sponsor Gruppo Italiano Studio Linfomi Centro Oncologico Modenese Policlinico di Modena via del Pozzo Modena

19 Bendamustine TREANDA

20 Bendamustine is a cytostatic drug that combines a purine-like benzamidazole nucleus with a bifunctional alkylating nitrogen mustard group. The drug was first synthesized in the 196s. Limited data were published during the initial period of investigation. It is active against a large panel of cell line. Tn the animal model Bendamustine showed a sinergistic interaction with Rituximab

21 Activity of Bendamustine All NHL types except T limphoma CLL Breast Cancer Small cell lung cancer

22 Activity as single agent in indolent lymphoma ORR = 7% DR = 6.7 months Friedberg et al, JCO 28 Activity in combination with Rituximab ORR = 9% PFS = 3 months Rummel data

23 Toxicity Neutropenia Thrombocitopenia Anemia Nausea-Vomiting Secondary cancer?

24 PROTOCOL SYNOPSIS Title A Phase II Study of chemoimmunotherapy with Rituximab, Bendamustine and Myocet followed by Rituximab in The Treatment Of Elderly Patients With advanced stage Follicular Lymphoma Study Phase Phase II Indication Untreated, advanced Follicular Lymphoma Primary Objectives Response Rate Safety Secondary Objectives DR, PFS, and OS molecular response (PCR assessment of t(14;18)) on bone marrow Number of sites and subjects A total of 46 evaluable patients accrued at xxxx Estimated study duration 18 months for the accrual phase and 3 months for the follow up phase Drug Dosage and Formulation Rituximab: (375 mg/m?bsa; day 1* / q3w) Bendamustine: (9 mg/m? BSA; day 1-2 / q3w) Myocet : (5 mg/m? BSA; day 1 / q3w) Prednisone: (1 mg/d (e.v or p.o.); day 1-5 / q3w) For 4-6 cycles? After one month: 2-4 infusion, or R every 3 weeks?

25 Bortezomib Velcade FDA: II line for MM end Mantle cell Lymphoma II line for MM EMEA:

26 Bortezomib alone ORLOWSKI, R.Z ET AL. PHASE I TRIAL OF THE PROTEASOME INHIBITOR PS-341 IN PATIENTS WITH REFRACTORY HEMATOLOGIC MALIGNANCIES. J CLIN ONCOL, 22. MILLENNIUM PHARMACEUTICALS, I.C.M., DATA ON FILE. 22. O'CONNOR O ET AL. PHASE II CLINICAL EXPERIENCE WITH THE PROTEASOME INHIBITOR BORTEZOMIB (FORMERLY PS-341) IN PATIENTS WITH INDOELNT LYMPHOMAS. ASCO 23. GOY AH ET AL. PHASE II STUDY OF PROTEASOME INHIBITOR BORTEZOMIB IN PATIENTS WITH RELAPSED OR REFRACTORY INDOLENT AND AGGRESSIVE B-CELL LYNOHOMAS. ASCO 23. PAPANDREOU C, D.D ET AL. PROTEASOME INHIBITOR PS-341 IN PATIENTS (PATIENTS) WITH ADVANCED MALIGNANCIES. ASCO 21

27 Phase II study of proteasome inhibitor Bortezomib in realpsed or refractory B-cell NHL... In arm B, among 21 assessable patients,, the ORR was 19%, with PRs (one patient with B-cell DLCL and one with WM) one CR (SLL) and one CRu (FL)... Goy A et al. JCO 25

28 Rationale for Bortezomib and Rituximab association SUZUKI E, J.A. ET AL. CHEMOSENSITIZATION OF DRUG AND RITUXIMAB-RESISTANT DAUDI B- NHL CLONES TO DRUG-INDUCED APOPTOSIS BY THE PROTEASOME INHIBITOR NPI-52. BLOOD, 25. DE VOS S, ET AL., BORTEZOMIB PLUS RITUXIMAB IN PATIENTS WITH INDOLENT NON- HODGKIN'S LYMPHOMA (NHL): A PHASE II STUDY. BLOOD, 25

29 FOLREC3 Study Diagnosis of RELAPSED or PROGRESSED Follicular Lymphoma VELCADE : 1,3 mg/m 2 day 1,4,8,11 2 cycles, every 21 days early evaluation of response all patients VELCADE : 1,3 mg/m2 day 1,4,8,11 4 cycles, every 21 days Rituximab: 375 mg/m2 day 1, cycle III, IV, V, VI; + two additional doses at week +3 final evaluation of response

30 De Vos S et al. Phase 2 Study of Bortezomib Weekly or Twice Weekly Plus Rituximab in Patients with Follicular (FL) or Marginal Zone (MZL) Lymphoma: Final Results. ASH 26 Johannes Drach J, Marked Activity of Bortezomib, Rituximab, and Dexamethason in Relapsed and Refractory Mantle Cell Lymphoma. ASH 26 GerecitanoJ et al. The Schedule Dependent Combination of Bortezomib (Bor) with Rituximab (R), Cyclophosphamide (C) and Prednisone (P) Produces Minimal Toxicity, Even at Relatively High Doses of Proteasome Inhibitor, in Patients with Relapsed/Refractory Indolent B-Cell Lymphomproliferative Disorders. ASH 26 Irene M. Ghobrial, Phase II Trial of Combination of Bortezomib and Rituximab in Relapsed and/or Refractory Waldenstrom Macroglobulinemia: Preliminary Results. ASH 26 Liang Zhang L et al, Bortezomib Is Synergistic with Rituximab and Cyclophosphamide in Inducing Apoptosis of Mantle Cell Lymphoma Cells In Vitro and In Vivo. ASH 27

31 Guariglia G et al. Combination of Rituximab, Bortezomib and Hyper- Fractionated Cyclophosphamide (RBC) in "True" Elderly Patients with Advanced Mantle Cell Lympoma. ASH 27 Blum A et al. Excessive Neurotoxicity in a Phase II Trial of Combined Bortezomib and Rituximab in Patients with Relapsed/Refractory Mantle Cell (MCL) and Follicular (FL) Non-Hodgkin s Lymphoma. ASH 27 Treon S et al. Bortezomib, Dexamethasone and Rituximab (BDR) Is a Highly Active Regimen in the Primary Therapy of Waldenstrom s Macroglobulinemia: Planned Interim Results of WMCTG Clinical Trial ASH 26 Drach J et al. Bortezomib, Rituximab, and Dexamethason (BORID) as Salvage Treatment in Relapsed/Refractory Mantle Cell Lymphoma: Sustained Disease Control in Patients Achieving a Complete Remission. ASH 27 A. Agathocleous A et al. Preliminary Results of a Phase I/II Study of Weekly or Twice Weekly Bortezomib in Combination with Rituximab, in Patients with Follicular Lymphoma, Mantle Cell Lymphoma and Waldenström s Macroglobulinaemia. ASH 27

32 ENZASTAURIN