La ricerca indipendente in oncologia tra vecchi farmaci e nuovi progressi. Alessandro Rambaldi

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1 La ricerca indipendente in oncologia tra vecchi farmaci e nuovi progressi Alessandro Rambaldi

2 Quale ricerca clinica per i bisogni clinici non risolti dei pazienti ematologici? La storia recente dell Ematologia è stata caratterizzata prevalentemente da bisogni clinici dei pazienti che hanno trovato una risposta prevalente grazie a ricerca clinica indipendente La ricerca (clinica e di laboratorio) non è un momento eccezionale della pratica medica È responsabilità dei ricercatori condurre sperimentazioni che rispondono ai bisogni dei pazienti, della scienza o del mercato

3 In Europe, clinical research must adhere to The Clinical Trials Directive (2001/20/EC) introduced in 2004 and The Good Clinical Practice Guidelines Directive introduced in 2005

4 Pros and Cons Both directives aim to harmonize administrative processes across EU member states, to protect patients, and to optimize the reliability of results Both take into account the perspective of large industry-led randomized clinical trials (RCTs) but neglect the vast experience in observational and interventional trials of cooperative groups In reality, the administrative burden for all studies has increased enormously Barbui, T et al.: haematologica 2012; 97(6)

5 Progressi in Ematologia Migliori strategie terapeutiche (con vecchi farmaci) Sviluppo della genetica molecolare Trapianto di cellule staminali emopoietiche e terapie cellulari I nuovi farmaci

6 Storia del trattamento della ALL del bambino: un paradigma nella cura del cancro

7 Survival 1.0 AIEOP B lineage 2210 patients N. pts N. deaths yrs Surv iv al 8 yrs Surv iv al 90.3% (0.8) 88.7% (0.9) 94.3% (0.8) 93.2% (1) YEARS FROM DIAGNOSIS CORS - Jul 2010 Overall Survival in B-precursor ALL

8 Frequency of cure in childhood ALL Available drugs since 70s Prednisone Cyclophosphamide Vincristine Adryamicin L-Asparaginase Cytarabine Methotrexate 6-Mercaptopurine Simone JV, Best Practice & Research Clinical Haematology, 19: , 2006

9 Le ragioni di questi risultati Intensità della terapia anti leucemica e di supporto Organizzazione della cura (degenza e day-hospital) Nessun paziente fuori da un protocollo di studio! Le nuove figure professionali della medicina

10 p-survival (%) p-morbidity (severe) (%) p-mortality (treatment reltaed) (%) 100 Childhood ALL: The Treatment Dilemma Status at the end of the 1990's Treatment intensity (number of drugs combined, dose intensity) Schrappe M., 2008

11 Lo sviluppo della genetica molecolare

12 Acute promyelocytic leukemia AML: FAB M3 / M3v 25% in latins 10% in anglo-saxons D.I.C., haemorrhages low WBC count ATRA t(15;17) PML-

13 Main outcomes of APL treatment Lo Coco et al.: N Engl J Med 2013;369:111-21

14 Alcuni dettagli di questi studi Sponsor Conduzione GCP? Assicurazione? Monitoraggio? Costi? AIEOP-GIMEMA-NILG etc.. No (fino a poco tempo fa) No No Bassissimi (quasi interamente sostenuti dalle associazioni di volontariato e da modesti grant di ricerca)

15 Trapianto di cellule staminali e terapie cellulari

16 E. Donnal Thomas Poor kid from Texas, attended Harvard Med School Tested various transplant techniques in dogs Tested them in patients with late stage leukemia (1957) Every patient who underwent transplantation died during the procedure of shortly thereafter. After 4 years stopped human trials. Things were pretty grim. 8 years later, identified genetic markers of histocompatibility Enabled close matching of donor and recipient Led to successful results in dogs Resumed human trials, led to successful treatment for leukemia Received the Nobel Prize in 1990

17 2500 GITMO Trapianto Allogenico Allotrapianti registrati (N=27245) < ANNI

18 Cumulative survival Allo-HSCT from 2000 to 2008 in AML patients (age 40-55, 1st or 2nd CR). n=669, 0,50 at 10 yrs years Overall Survival

19 Cumulative Incidence Non relapse mortality Years

20 Randomized study comparing intravenous Busulfan (I.V. BU; BUSILVEX ) plus Fludarabine (BUFLU) versus intravenous Busulfan plus Cyclophosphamide (BUCY2) as conditioning regimens prior to allogeneic hematopoietic stem cell transplantation in patients (aged 40 and 65 years) with AML in complete remission Alessandro Rambaldi Principal Investigator Protocol GITMO AML R.2 EudraCT number: ClinicalTrial.gov Identifier:NCT

21 CONTRATTO PER L ESECUZIONE DEI PROGETTI DI RICERCA INDIPENDENTE SUI FARMACI Si conviene e si stipula quanto segue Art. 7- Modalità di erogazione del contributo L AIFA contribuisce alla realizzazione del progetto di studio approvato mediante un contributo, finalizzato alla copertura delle spese necessarie allo svolgimento dell attività di ricerca, pari a Euro ,00 (duecentocinquantamila/00).

22 Prospective comparison IV FB4 vs IV BuCy2 CMNS 24 Italian BERGAMO, Ospedali Riuniti MILANO - Ospedale Maggiore MILANO-Istituto Nazionale dei Tumori BRESCIA - AO Spedali Civili di Brescia - USD-TMO MONZA - Osp. S. Gerardo de' Tintori VICENZA- Ospedale S.Bortolo UDINE-Policlinico Universitario BOLZANO - Ospedale Regionale Generale GENOVA - Ospedale San MartinoTORINO, San Giovanni Battista ALESSANDRIA, Azienda Ospedaliera SS Antonio e Biagio CUNEO Az Osp. S.Croce e Carle FIRENZE - A.O.U. Careggi ANCONA-Ospedali Riuniti SIENA-Az. Osp. Univers. Senese ROMA - Policlinico A. GemelliROMA - Universita' La Sapienza ROMA-Policl inico Universitario Tor Vergata PESCARA - Ospedale Civile BARI-Policlinico S.GIOVANNI ROTONDO Casa Sollievo della Sofferenza NAPOLI - AOU Policlinico Federico II PALERMO-Osped.V.Cervello 1 Israel TEL HASHOMER, (Prof Arnon Nagler)

23 Study design STRATIFICATION Related vs Unrelated Donors CR1 vs CR2 or more RANDOMIZATION N=240 Arm A, N=120 I.V. BuFlu Expected TRM at 1y after HSCT: 12.5% Arm B, N=120 I.V. BuCy2 Estimated TRM at 1y after HSCT: 25% SAMPLE SIZE CALCULATION: alpha=0.05; beta=0.2; two-sided test

24 Randomization

25 1,00 GITMO AML R2 Overall Survival (N = 245) Death 95/245 (38.8%) 0,75 0,50 0,25 0,00 Patients at risk (Events) 245 (62) 163 (23) 92 (7) 54 (1) 22 (1) 3 (-) Years

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27 Survival according to GVHD grade M. Introna et al. / Biol Blood Marrow Transplant 20 (2014) Rambaldi A.: Educational Session EBMT

28 Innovative treatments for refractory/resistant acute leukemias

29 When allogeneic transplant fails Cellular Therapy with CIK cells Restricted CIK cell killing TCR + +? MHC I Non MHC-restricted killing Target cell Tumor cell Cytokine-induced killer (CIK) cells are NK-T cells (CD56+CD3+) expanded from peripheral blood mononuclear cells Cells with the phenotype CD56+CD3+ were first described in NK cell clones by T. Hercend CIK cells show non-specific anti-tumoral activity and home to tumors without significant GVHD in several animal models

30 Sequential Infusion of Unmanipulated Donor Lymphocytes and Cytokine Induced Killer (CIK) cells after allogeneic stem cell transplantation PROTOCOL CIK2 Version 3.0, 30/Jul/2009 EudraCT number: ClinicalTrials.gov: NCT AIFA and ISS approved Participating centers: USC Hematology, Ospedali Riuniti di Bergamo Hematology, Ospedale di Bolzano Hematology, Ospedale San Gerardo di Monza, Italy

31 Chimeric antigen receptors. Maus M V et al. Blood 2014;123: by American Society of Hematology

32 CD3andAnti-CD19ChimericAntigenReceptorinPeripheralBlood

33 Relative therapeutic potential of cellular therapies for relapse DeLima et al.: BBMT(2013)

34 Cell based strategies to manage leukemia relapse: efficacy and feasibility of immunotherapy approaches The use of cellular therapies opens up new opportunities for the deepest molecular eradication of these diseases and potentially their definitive cure. Several problems are still to be addressed The emergence antigen negative leukemic cells which will rapidly expand into a complete resistant clone. The safety of these cells has not been yet convincingly proven. The laboratory requirements. Until automation is introduced, the preparation of these cells will be only feasible in highly specialized laboratory facilities, most likely under the control of pharmaceutical companies It is not difficult to imagine that the economic costs of these laboratory procedures would be extremely high, presenting questions of affordability for a significant number of patients. Alessandro Rambaldi et al.: Leukemia 2014, in press

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36 Ways to improve clinical research activity in Europe Barbui, T et al.: haematologica 2012; 97(6)

37 Ways to improve clinical research activity in Europe Barbui, T et al.: haematologica 2012; 97(6)