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La ricerca indipendente in
oncologia tra vecchi farmaci e
nuovi progressi
Alessandro Rambaldi
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
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
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)
Progressi in Ematologia
• Migliori strategie terapeutiche (con vecchi
farmaci)
• Sviluppo della genetica molecolare
• Trapianto di cellule staminali emopoietiche e
terapie cellulari
• I nuovi farmaci
Storia del trattamento della
ALL del bambino:
un paradigma nella cura del cancro
AIEOP 95-2000
B lineage
2210 patients
1.0
Survival
0.8
0.6
0.4
N. pts
1241
969
95
2000
0.2
N. deaths
140
56
5 yrs Surv iv al 8 yrs Surv iv al
90.3% (0.8)
88.7% (0.9)
94.3% (0.8)
93.2% (1)
0.0
0
1
2
3
4
5
6
7
8
YEARS FROM DIAGNOSIS
CORS - Jul 2010
Overall Survival in B-precursor ALL
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: 353–359, 2006
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
50
80
40
Status at the end
of the 1990's
60
30
40
20
20
10
0
0
10
0
Treatment intensity (number of drugs combined, dose intensity)
Schrappe M., 2008
p-Mortality (treatment reltaed) (%)
100
p-Morbidity (severe) (%)
p-Survival (%)
Childhood ALL: The Treatment Dilemma
Lo sviluppo della genetica
molecolare
Acute promyelocytic leukemia
AML:
FAB M3 / M3v
25% in latins
10% in anglo-saxons
D.I.C., haemorrhages
low WBC count
t(15;17)
ATRA
PML-
Main outcomes of APL treatment
Lo Coco et al.: N Engl J Med 2013;369:111-21
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)
Trapianto di cellule staminali e
terapie cellulari
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
GITMO Trapianto Allogenico
Allotrapianti registrati
(N=27245)
2500
2083
2000
1763
1686
1684
1598
14911493
14201449
1315 1299
1216
1165
1066
1057
1500
1000
886
669
500
368
446 472
743 785
533 558
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
20
09
20
10
20
11
20
12
20
13
19
96
19
95
19
94
19
93
19
92
19
91
<1
99
1
0
ANNI
Allo-HSCT from 2000 to 2008 in AML patients
(age 40-55, 1st or 2nd CR)
0.75
0.25
0.50
n=669, 0,50 at 10 yrs
0.00
Cumulative survival
1.00
.
0
2
4
6
8
10
years
Overall Survival
12
14
0.8
0.6
0.4
0.2
0.21
0.24 0.25
0.0
Cumulative Incidence
1.0
Non relapse mortality
0
2
4
6
Years
8
10
12
14
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: 2007-005803-16
ClinicalTrial.gov Identifier:NCT1191957
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 250.000,00 (duecentocinquantamila/00).
Prospective comparison IV FB4 vs IV BuCy2
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


24 Italian



CMNS
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
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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)
Study design
STRATIFICATION
Related vs Unrelated Donors
CR1 vs CR2 or more
RANDOMIZATION
N=240
Arm A, N=120
Arm B, N=120
I.V. BuFlu
I.V. BuCy2
Expected TRM at 1y
after HSCT: 12.5%
Estimated TRM at 1y
after HSCT: 25%
SAMPLE SIZE CALCULATION:
alpha=0.05; beta=0.2; two-sided test
Randomization
GITMO AML R2
Overall Survival (N = 245)
1,00
Death 95/245 (38.8%)
0,75
0,50
0,25
0,00
Years
0
Patients at risk (Events)
245
(62)
1
163
2
(23)
92
3
(7)
54
4
(1)
22
5
(1)
3
6
(-)
-
Survival according to GVHD grade
M. Introna et al. / Biol Blood Marrow Transplant 20 (2014) 375-381
Rambaldi A.: Educational Session EBMT 2014
27 27
Innovative treatments
for refractory/resistant acute leukemias
When allogeneic transplant fails
Cellular Therapy with CIK cells
Restricted
killing
MHC I
Target
cell
•
•
•
TCR
CIK cell
+
+
?
Non MHC-restricted
killing
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
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: 2008-003185-26
ClinicalTrials.gov: NCT01186809
AIFA and ISS approved
Participating centers:
• USC Hematology, Ospedali Riuniti di Bergamo
• Hematology, Ospedale di Bolzano
• Hematology, Ospedale San Gerardo di Monza, Italy
Chimeric antigen receptors.
Maus M V et al. Blood 2014;123:2625-2635
©2014 by American Society of Hematology
CD3andAnti-CD19ChimericAntigenReceptorinPeripheralBlood
Relative therapeutic potential of cellular
therapies for relapse
DeLima et al.: BBMT(2013)
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
Ways to improve clinical research activity
in Europe
Barbui, T et al.: haematologica | 2012; 97(6)
Ways to improve clinical research activity
in Europe
Barbui, T et al.: haematologica | 2012; 97(6)

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