TUMORI UTERINI MESENCHIMALI

Studi clinici in corso sulle
nuove cure del mesotelioma
Federica Grosso
[email protected]
incidenza
incidenza ~ 1,5 - 2 /100.000/anno
~
1400 /anno
Montanaro F et al, Int J Cancer 2009
Problemi dei tumori rari
 Ricerca clinica
 esiguità del campione e Q evidenza
 Decisione clinica
 Carenza di evidenza + difetto di
esperienza
 Assistenza
 Q cura difficile da mantenere
Wagner JC et al, Brit J industr. Med 1960
# 230 nuovi casi/anno
 50-90 distretto AL3
CPO Piemonte
Casalese 1990-2006
incidenza ~ 57/100.000/anno
~ 33/100.000/anno
www.cpo.it/dationcologici/rmm2007.htm
Marinaccio et al, Int. J. Cancer 2005
aree di ricerca

Malattia localizzata/operabile




Chirurgia
Chemioterapia
Radioterapia
Malattia avanzata/non operabile




Chemioterapia di prima linea
Terapia a bersaglio molecolare
Popolazioni speciali
Valutazione della risposta
Distribuzione per stadio alla
diagnosi
Stadio I-II 25%
Stadio III 40%
Francart J et al, EJC 2009
chirurgia



si o no
EPP o P/D
Neoadj vs Adj
Treasure T, Lancet Oncol 2011
The Pass trial
Pleural mesotheliomA Strategies Study
Pleurectomia/
decorticazione
DDP+PMTx4
VATS+pleurodesi
R
TC T/A + TC-PET
+/- RM
#120 pz
Follow-up
24 mm
60 mm durata
Endpoint: OS
PFS-QoL-complicanze
INT Milano
radioterapia



Ruolo dopo EPP
Ruolo dopo P/D
Nella malattia non resecabile?
Phase II toxicity study using CT +/- P/D followed by
IMRT to the pleura in pts with locally advanced MPM
(NCT00715611). MSKCC
4 cycles
CDDP-PEM
Or
CBDCA-PEM
4-6 weeks
4-8 weeks
IMRT
50.4Gy/28fr
+/- P/D
28 pts
SECONDARY ENDPOINTS:
PRIMARY ENDPOINT:
To determine the safety by the incidence of pneumonitis G≥3.
RR, PFS, and OS rates
Local recurrence versus metastatic disease.
Incidence of any G≥3 toxicity.
www.clinicaltrials.gov
Neoadjuvant CT and EPP of MPM with or without
hemithoracic RT. A Randomized Multicenter Phase II
Trial
(NCT00334594) Swiss Group for Clinical Cancer
Research
3 cycles of CDDP-PEM
PRIMARY ENDPOINTS:
1.
2.
Evaluate the short-term outcomes and
feasibility of neo-adjCT followed by EPP.
Evaluate the long-term outcomes and
feasibility of PORT in pts with R0 or R1.
EPP
155 pts
R
IMRT
FU
www.clinicaltrials.gov
17
OR 41%
vs 16%
PFS 5.7
OS 13.3



+ nuovi farmaci
selezione
mantenimento
+ bevacizumab



Iperespressione di VEGFR
Alti livelli di VEGF circolante
Associazione con peggiore outcome
Author
Regimen
Phase
Status
N
pts
RR/DCR
PFS
OS
Kindler et al.
JCO 2012
Cis/Gem/Bev
Cis/Gem/Pla
II R
Completed
53
55
24.5% / 75.5%
21.8% / 81.8%
6.9 mo
6.0 mo
15.6 mo
14.7 mo
Dowell et al.
IASLC 2009
Cis/Pem +
Beva
II
Completed
43
43% / 81%
6.9 mo
14.8 mo
Ceresoli et al.
Submit JCO
Carbo/Pem +
Beva
II
Completed
77
34.2% / 92.1%
6.9 mo
15.3 mo
Zalcman et al.
ASCO 2010
Cis/Pem/Bev
Cis/Pem/Pla
II R-III R
Phase II
completed
47
57.4%
45.7%
(DCR at 6 mo)
NR
NR
c-MET pathway and c-MET
signaling inhibition strategies
Eder JP et al. Clin Cancer Res 2009;15:2207-2214
+ tivantinib – fase I/Ib


ICH cMET
75-100% MM
HGF nel liquido
pleurico
CBDCA+PMT+Tivantinib
+ nintedanib (BIBF1120) – fase II
# 43 pz
DDP+PMT
+BIBF1120 X6
R
# 43 pz
#86 pz
BIBF1120
… PD
DDP+PMT
+PLACEBO X6
plecebo
Selezione dei pazienti

Bassi livelli di timidilato
sintetasi predicono un
miglior outcome

Standardizzazione delle
tecniche diagnostiche
Validazione in studi
prospettici

Zucali, CCR 2011
Righi, JCO 2010
mantenimento



Mantenere il
beneficio clinico
ottenuto con la
CT
con CT
con altri farmaci
DRUG
phase
N° pts
mPFS
mOS
PEMETREXED
Observation
II R
27
6.0 mos
3.4 mos
17.9 mos
8.5 mos
THALIDOMIDE
Observation
III R
222
16 wks
15 wks
11 mos
13 mos
Studi in corso
DRUG
phase
N° pts
www.clinicaltrails.gov
PEMETREXED
Observation
II R
96
NCT01085630
NGRhTNF
Placebo
III R
100
NCT01358084
NGR-hTNF NGR019
NGRhTNF
DDP/CBDCA+PMTx6
R
SD
OR
#100
… PD
Placebo
Seconda linea
Seconda linea
PI3K/AKT/mTOR pathway
Growth factors
including
IGF-1, VEGF, ErbB

PI3-K
Oxygen,
energy, and
nutrients
PTEN
Akt
Estrogen
receptor

TSC2 TSC1
Ras/Raf
pathway
kinases
mTOR

S6K1
S6
Protein production
Cell growth
and
proliferation
Nutrient
uptake and
metabolism
4E-BP1
elF-4E
Angiogenesis
mTOR is a ser/thr
kinase
mTOR is a central
regulator of multiple
signaling pathways
involved in cancer
mTOR regulation can
affect: Angiogenesis;
Cell growth; Nutrient
uptake, utilization;
Metabolism
“..We show that in queen-destined larvae, the TOR inhibitor
rapamycin induces the development of worker characters..”
Merlin regulates mTOR
signaling pathway in MM
cells
Sekido Y. Cancer Sci. 2010; 101:1
GDC0980
GDC0980
R
1:1
1 o 2 previous line
P+PMT
#380
Vinorelbina
tremelimumab
Courtesy of L. Calabrò and M. Maio
IMIG 2012
Courtesy of L. Calabrò and M. Maio
IMIG 2012
Mesoteliomi sarcomatoidi
desmoplastici
8-15%
Median OS = 7,5 mos
(IQR 4,5-13,6)
Trabectedin (ET-743)

Tetrahydroisoquinoline

marine compound with antitumor activity
isolated from the caribbean tunicate

EMA 2007

Ecteinascidia turbinata
Valutazione della risposta
Valutazione volumetrica
Fan Liu, JTO 2010
LA STAMPA 22 Aprile 2012
Analisi del genoma
www.meso.ospedale.al.it
[email protected]
GIC mesotelioma interaziendale Alessandria – Casale Mto