Istotipi “frequenti”: Aggiornamento protocolli A

 Il




problema dei tumori rari è socialmente rilevante,
paradossalmente proprio in termini quantitativi, oltre
naturalmente a costituire una priorità per motivi etici.
Sotto il profilo etico, infatti, non è giusto che i pazienti con tumore
raro abbiano a soffrire discriminazioni dovute alla bassa incidenza
della loro malattia, come invece può accadere.
I tumori rari, come le malattie rare in genere, comportano
difficoltà particolari.
Le competenze cliniche sui tumori rari non sono reperibili con
facilità dalla persona malata, in quanto i centri che ne dispongono
sono pochi e dispersi geograficamente.
Inoltre, il trattamento dei tumori rari richiede spesso approcci
multidisciplinari, e dunque la dispersione geografica delle
competenze risulta ancora più frequente.
Di fatto, i tumori rari sottendono un elevato grado di migrazione
sanitaria, all'interno e verso l'esterno del Paese: i costi sociali sono
impressionanti
Anche i costi sanitari vengono impattati dai tumori rari.
Sono frequenti delle prestazioni improprie al di fuori dei centri di
riferimento.
Esse possono incidere sfavorevolmente sulla prognosi dei Pazienti, e
questo costituisce il principale problema etico.
Ma, anche qualora la prognosi possa essere mantenuta invariata
attraverso successivi interventi "di salvataggio", rimane una
moltiplicazione dei costi.
Lo sviluppo dei nuovi farmaci nei tumori rari è tutelato dalle
normative sui farmaci "orfani", che prevedono incentivi
economici per le aziende che ne ottengano la registrazione.
Perché questo avvenga, è però necessario effettuare studi
clinici, e dunque raccogliere casistiche di sufficiente numerosità
da avviare a studi clinici formalizzati.
Per migliorare la qualità di cura nell'ambito dei tumori rari,
sono obiettivi primari:
• Assimilare la diagnosi e il trattamento secondo criteri
comuni
• Realizzare la condivisione a distanza di casi clinici fra i centri
• Promuovere un razionale accesso alle risorse di diagnosi e
cura
Attraverso il perseguimento degli obiettivi primari, si intende
anche:
• contribuire alla ricerca clinica sui tumori rari;
• contribuire alla diffusione della conoscenza sui tumori rari;
• fungere da modello metodologico e tecnologico per la
collaborazione in rete geografica nell'ambito oncologico e
delle malattie rare.
Un Paziente che venga trattato direttamente presso la Struttura
Specializzata può:
• Ricevere un trattamento convenzionale, nell’ambito delle linee
guida consolidate
• Ricevere un trattamento fortemente individualizzato, in rapporto
a peculiarità del caso singolo
• Ricevere un trattamento all’interno di uno studio clinico (ad
esempio su un nuovo farmaco o su una strategia terapeutica
innovativa)
.
TRATTAMENTO MEDICO
Relative frequency of soft tissue
sarcoma subtypes
Leiomyosarcoma
3%
Malignant fibrous
histiocytoma
Liposarcoma
24%
Synovial sarcoma
36%
Rhabdomyosarcoma
9%
Angiosarcoma
Kaposi's sarcoma
Fibrosarcoma
5%
12%
2%
2% 5%
2%
17
Survival in advanced soft tissue sarcoma


The prognosis is usually poor for patients with locally advanced or metastatic
STS
5-year survival in patients presenting with distant metastases or after metastatic
relapse is ~16%
Survival in patients with STS after local or metastatic relapse
Patients with local recurrence/metastases
after surgery and radiotherapy (n=402)
Disease-specific
survival (%)
5 years
10 years
Overall
25
19
Isolated recurrence
48
46
Metastatic relapse
16
10
Retrospective study of 402 consecutive patients sustaining a first relapse of sarcoma after combined surgery and
radiotherapy. Median follow-up after relapse: 6.8 years
18
5-year survival in soft tissue sarcoma
varies depending on histological subtype
5-year survival in patients ages ≥20 years presenting with STS (all stages)
100
5-year survival (%)
80
60
40
20
0
Chemioterapia in adiuvante
Slide11
Slide12
Slide27
Slide28
trial design, group 1
histology-driven chemo x 3
LMS: GEM + DTIC
Mixoyd Liposarcoma: trabectedin
Synovial sa: HD-IFX
MPNST: IFX + VP16
Pleiomorphic : GEM + TAX
R



high grade
deep seated
>5 cm
EPI+IFO x 3
 Surgery + RT
 Surgery + RT
trial design, group 2



high grade
deep seated
>5 cm
EPI+ IFO x 3
 Surgery + RT
myxofibrosarcoma
pleomorphic liposarcoma
unclassified spindle cell sarcoma
pleomorphic rabdomyosarcoma
trial design, group 1
+ RT
histology-driven chemo x 3
synovial sa: HD-IFX
MPNST: IFX + VP16
 Surgery
R
+ RT
EPI+IFOx 3
 Surgery
trial design, group 1
+ RT
EPI+IFOx 3
LMS
MRCLPS
UPS
 Surgery
trial design, group 2
+ RT
epiADM+IFX x 3
 Surgery
myxofibrosarcoma
pleomorphic liposarcoma
unclassified spindle cell sarcoma
pleomorphic rabdomyosarcoma
tumor response





MRI (morphologic + functional study)
CT (only when MRI is contraindicated)
PET scan
DCEUS
path evaluation
timing of radiological assessment:

baseline, after one cycle, just before surgery
trial status in Italy
Site
Current status
Amendment 1
Enrollment status
(n. pts)
INT, Milano (001)
Open
Approved
28
IOR, Bologna (002)
Open
Approved
30
IRCCS Candiolo (003)
Open
Approved
3
Gradenigo (004)
Open
Approved
2
IRST, Meldola (005)
Open
Approved
2
IOV, Padova (006)
Open
Approved
6
CRO, Aviano (007)
Open
Approved
4
IEO, Milano (008)
Open
Approved
2
Humanitas, Milano (009)
Open
Approved
13
Brescia (010)
Open
Waiting for EC
1
IFO, Roma (011)
Open
Approved
5
Pascale, Napoli (012)
Open
Waiting for EC
-
Waiting for EC approval
Waiting for EC
-
Careggi, Firenze
trial status in Spain
Site
Current status
Amendment 1
Enrollment status (n. pts)
H. SON ESPASES, P. MALLORCA (101)
Open
Approved
6
H. SANT PAU, BARCELONA (102)
Open
Approved
11
H. V.HEBRON BARCELONA (103)
Open
Approved
3
H. VICTORIA; MALAGA (104)
Open
Approved
1
LA PAZ, MADRID (105)
Open
Approved
4
TENERIFE (106)
Open
Approved
-
IVO, VALENCIA (107)
Open
Approved
-
M. SERVET, ZARAGOZA (108)
Open
Approved
1
MD ANDERSON, MADRID (109)
Open
Approved
-
H. ROCIO, SEVILLA (110)
Open
Approved
1
H. LA FE, VALENCIA (111)
Open
Approved
-
NAVARRA, PAMPLONA (112)
Open
Approved
-
H. RAMON y CAJAL, MADRID
Open
Approved
-
H. ASTURIAS, OVIEDO
Open
Approved
-
H. COMPOSTELA
Open
Approved
-
H. BASURTO, BILBAO
Open
Approved
-
H. VALDECILLA, SANTANDER
Open
Approved
-
H. PUERTA HIERRO, MADRID
Open
Approved
-
trial status in Poland and France
Sites
Current Status
Enrollment status
(n. pts)
Open
1
PARIS (2 SITES)
Waiting for CA
-
LYON
Waiting for CA
-
GRENOBLE
Waiting for CA
-
MARSEILLE
Waiting for CA
-
RENNES
Waiting for CA
-
CLERMONT-FERRAND
Waiting for CA
-
SAINT-HERBLAIN
Waiting for CA
-
STRASBOURG
Waiting for CA
-
VILLEJUIF
Waiting for CA
-
PL – WARSAW (301)
Ruolo della chemioterapia nella malattia avanzata
Slide15
Istotipi “frequenti”: Aggiornamento protocolli
Y-IMAGE: a non-interventional multicenter, prospective study to
evaluate treatment outcome assessment methods used in routine
clinical practice on patients with advanced soft tissue sarcoma treated with
trabectedin according to the Summary of Product
Characteristics
 This non-interventional, prospective, observational phase IV study will
estimate the PFS at 6 months based on RECIST and/or Choi criteria in real-life clinical
practice using trabectedin for the management of advanced soft tissue
sarcoma

Patients with advanced or metastatic histologically-proven STS with measurable
disease with a baseline tumor evaluation by RECIST and/or Choi criteria


47 centres globally, 251pts will be selected
Primary endpoint: PFS at 6 months per RECIST and/or Choi criteria
Secondary endpoints: PFS at 12 months, OS, ORR, TTP, Duration of response, GMI
where information about a previous therapy’s TTP is available
Abstract ID: 2331465
Final ID: Poster 120
CTOS 2015
Y-IMAGE STUDY: A NON-INTERVENTIONAL, PROSPECTIVE PHASE IV STUDY OF TRABECTEDIN IN PATIENTS
WITH ADVANCED SOFT TISSUE SARCOMA (STS)
Penel Nicolas1, Buonadonna Angela2, Benson Charlotte3, Casanova Jose4, Kasper Bernd5, Nadal José
Alberto6, López Pousa Antonio7, Mazzeo Filomena8, Brodowicz Thomas9
BACKGROUND
RESULTS
TREATMENTS
 Trabectedin (Yondelis®) is the first marine-derived drug approved in Europe for
the treatment of adult patients with advanced STS, after failure of
anthracyclines and ifosfamide, or who are unsuited to receive these agents.
 It acts as a DNA-binding agent and it has been proposed to have antiinflammatory properties and unique modulatory effects on the tumor microenvironment, attributed to its effect on tumor-associated macrophages and
histiocytes [1-3]. Case-reports or post hoc analysis from clinical trials have
suggested that trabectedin can show atypical radiological responses, such as
massive central tumor necrosis [4] or tumor calcification [5], associated with
clinical improvement.
 Assessment of tumor response to trabectedin should include tumor shrinkage
(Response evaluation criteria in solid tumors; RECIST), but may also include
tumor density changes (Choi criteria). Implementation of Choi and RECIST in a
standardized manner remains a challenge in real life practice. A retrospective
comparison of trabectedin response evaluated by RECIST/Choi criteria showed
that Choi criteria may identify some cases of false progression underlining the
importance of correct definition of tumor progression in the decision making
strategy for treatment discontinuation [6].
 In order to evaluate the use of trabectedin in STS and its response evaluation by
RECIST /Choi criteria in real-life practice, an international, prospective, noninterventional study was designed.
erapy
Median
n
199
%
91.7
119
54.8
1 (0-6)
(range)
Female
Age
(years)
Median
(range)
%
43.
3
56.
123
7
58 (2179)
132 (63.2%)
0.2
0.1
0.0
0
2
4
6
8
10
12
In-patients
60 (28.7%)
Trabectedin exposure; n=217
Cycles at
Median (range)
enrollment
Median total
trabectedin exposure
Cycles per patient
(range)
(Y-IMAGE)
%
39.2
1
68
31.3
2
13
6.0
3
1
0.5
50
23.0
16
18
20
22
24
≥6 cycles
Median (range),
months
Histology; n=217
27 sarcoma
subtypes
Leiomyo
sarcoma
Liposarc
oma*
Synovial
sarcoma
Pleomor
phic
Fibromyx
*Including myxoid
liposarcomas
osarcoma
Chondro
sarcoma
Angiosar
coma
At the time of the cut off all the patients had
at least one evaluation except 8 patients that
were imputed as not available and 59 of these
evaluations were clinical.
1.0
CHOI (N=44 C=18)
RECIST (N=44 C=15)
Censored
Censored
0.9
0.8
0.7
Intra-patient comparison of PFS; Median
PFS
0.6
0.5
RECIST: 8.1 months (95% CI: 5.3-10.7)
0.4
Retrospective CHOI: 15.3 months (95% CI:
6.9-21.2)
0.3
n
14
Time (months)
Intra-patient comparison of RECIST vs. retrospective Choi evaluation in 44 patients revealed a differential PFS
response with median 15.3 months (95% CI: 6.9-21.2) by Choi vs. 8.1 (95% CI: 5,3-10,7) by RECIST.
Median number of trabectedin cycles received per patient was 6 with 56% patients
receiving ≥6 cycles and up to a maximum of 44 cycles. Median treatment duration
was 5.5 months
n
UN
PFS at 6 months: 46.9% (95% CI: 40.4%53.8 %)
0.3
Cumulative probability
Out-patients
Both
17 (8.1%)
NOTE: The in-patient / out-patient information was recorded
only starting on cycle 2 and onwards (8 patients that receive
only one cycle).
94
K
0.4
n (%)
n (%)
0.2
0.1
2 (2-29)
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
51
Time (months)
6 (1-44)
SAFETY
121 (55.8%)
•
5.5 (0.7-44.2)
Overall, 217 patients were enrolled from 11/2011-6/2014 (123 female) from 41 Among 27 sarcoma histotypes as defined by investigators main subtypes were
European centers. Median age of patients was 58 years (range: 21-79) and 70.5% leiomyosarcoma (41.9%), liposarcoma (23.5%) and synovial sarcoma (10.6%).
had ECOG performance status 0/1.
Male
PFS at 3 months: 69.4% (95% CI: 63.2%75.7%)
0.5
Progression-Free Survival RECIST and Choi
Type of treatment; n=209
Time on treatment
Gender
0.6
28.7%; both: 8.1%).
DEMOGRAPHICS
16.1% received trabectedin for 1 year or more
Demographics; n=217
Median PFS: 5.5 months (95% CI: 4.8-7.1
months)
0.7
0
22
10.1
1
87
40.1
2
74
34.1
3
22
10.1
4-6
12
5.6
Most patients were treated on an outpatient basis (outpatient: 63.2%; inpatient:
85
With 166 PFS events recorded, median PFS
was 5.5 months (95% CI: 4,8-7,1 months) as
assessed by RECIST (n=178), Choi (n=6) or
clinically (n=59). At 3 and 6 months, 69.4%
and 46.9% of patients were progressionfree and 16.1% received trabectedin for 1
year or more.
Yondelis (N=217 C=51)
Censored
0.8
Cumulative probability
Surgery
Radioth
Prior chemotherapy
lines
• The Y-IMAGE study evaluates trabectedin use in real-life clinical practice across
Europe, aiming to compare radiological response assessments obtained by
RECIST or Choi criteria.
• Data from adult patients with STS treated in 41 European centers with
trabectedin within the approved schedule (1.5 mg/m2; 24-h i.v. infusion every 3
weeks) have been collected in a non-interventional phase IV study. To be
included patients must have received at least 1 cycle of trabectedin and
currently be on treatment before their inclusion in the study.
Primary objective
The primary endpoint is progression-free survival (PFS) as defined by investigator’s
assessment (per RECIST and/or Choi criteria),
Secondary objectives
Secondary endpoints include objective response rate (ORR), disease control rate
(DCR), overall survival (OS) and safety.
Aim
Here we present the interim analysis of the primary endpoint at the cut-off of
March 20th 2015.
0
1.0
0.9
n=217
Prior treatments
METHODS
ECOG PS;
n=217
Kaplan-Meier plot of progression-free survival (PFS) by investigator’s assessment
Patients had received a median of 1 prior line of chemotherapy (range: 0-6), mostly
with anthracyclines ± ifosfamide (83.9%), whereas 22 (10.1%) patients were
chemotherapy-naïve at study entry.
n
%
91
41.9
51
23.5
23
10.6
8
3.7
6
2.8
3
1.4
2
0.9
•
•
•
Most common grade 3/4 adverse reactions were neutropenia and transaminase
increase, reported in 17.9% and 7.9% of patients, respectively.
Febrile neutropenia was reported in 2.7% of patients.
Fatigue (3.7% of patients), nausea (1.4%) and vomiting (1.4%) were the most
common trabectedin-related grade 3 adverse reactions.
A fatal case of drug-related pulmonary embolism was registered.
CONCLUSION
Trabectedin demonstrates long-term efficacy when used in real
practice to treat adult subtypes of STS with a manageable safety
profile. Choi criteria, although not commonly used in clinical
practice, may reveal a differential pattern of response assessment
to trabectedin compared with RECIST
CTOS 2015
Y-IMAGE (elderly patients)
TRABECTEDIN IN ELDERLY PATIENTS WITH RECURRENT SOFT TISSUE SARCOMA (STS): AN INTERIM ANALYSIS OF A
NON-INTERVENTIONAL, PROSPECTIVE PHASE IV STUDY
Buonadonna Angela, Kasper Bernd, Blay Jean Yves, Fernandes Isabel, Eisterer Wolfgang,
Lopez Pousa Antonio, Benson Charlotte, Penel Nicolas
B Trabectedin (Yondelis®) is an antineoplastic drug of marine origin for the treatment of advanced STS after failure
of anthracyclines and ifosfamide or for patients who are not suitable to receive these agents.
M Data from adult STS patients treated with trabectedin have been collected in a real-life phase IV Y-IMAGE study.
Patients must have received at least one cycle of trabectedin and be on treatment before their inclusion in the
study. The primary endpoint is progression-free survival (PFS). The aim of this interim analysis is to evaluate the
efficacy of trabectedin in elderly patients with recurrent advanced STS.
R: From 11/2011 through 6/2014 217 patients from 41 European centers were treated (Table 1). Out of these, 62
patients aged ≥65 years and 13 of these aged ≥75 years. Baseline characteristics of elderly patients were similar to
the overall study population, except for a reduced frequency of synovial sarcoma (6.5% vs. 12.3%) and better ECOG
PS score of 0/1 (61.3% vs 74.2%) observed in younger patients. Twice as many patients aged ≥65 received
trabectedin as first-line treatment that in the younger cohort (16.1% vs 7.7%). Median number of trabectedin
cycles per patient was 5 in and 4 in patients aged ≥65 and ≥75, respectively, reaching up a maximum of 44 cycles.
Sixty percent (37/62) of patients aged ≥65 were treated on an outpatient basis, similar to the 61% in younger
population (95/156). Nearly all patients aged ≥75 (11/13) received trabectedin as an outpatient treatment. Median
PFS was 4.1 months in patients aged ≥65 and 3.3 months in patients aged ≥75 years. A comparable number of
patients were progression-free at 3 and 6 months regardless of age (Table 1). Trabectedin was generally well
tolerated with no evidence of cumulative toxicity or end-organ dysfunction across all age groups.
C: This analysis demonstrated that trabectedin is an efficacious and well tolerated
treatment
in
young
and
elderly
patients
with
STS.
CTOS 2015
Y-IMAGE (early lines)
EFFICACY AND SAFETY OF TRABECTEDIN AS AN EARLY TREATMENT FOR ADVANCED STS: AN INTERIM ANALYSIS OF A
NON-INTERVENTIONAL, PROSPECTIVE PHASE IV STUDY
Mazzeo Filomena, Blay Jean Yves, Maud Toulmonde, Kasper Bernd, Paolo Casali, Giacomo
Giulio Baldi, Umberto Basso, Guido Biasco, Buonadonna Angela, Giovannella Palmieri, Penel
Nicolas
Background: Trabectedin (Yondelis®) is a marine antineoplastic drug for the treatment of advanced STS after failure of
anthracyclines and ifosfamide or for patients who are not candidates to receive these agents.
Methods: Data from adult STS patients treated with trabectedin 1.5 mg/m2 given as 24-h i.v. infusion every 3 weeks have
been collected in a real-life phase IV Y-IMAGE study. To be included patients must have received at least 1 cycle of
trabectedin and be currently on treatment before their inclusion in the study. The primary endpoint is progression-free
survival (PFS). The aim of this interim analysis is to evaluate the efficacy of trabectedin when used in earlier lines of
treatment.
Results: From 11/2011-6/2014 217 patients from 41 European centers were treated (Table 1). Median number of
administered trabectedin cycles at enrolment was 2. Before trabectedin patients were pretreated with a median of 1 prior
line of chemotherapy (range: 0-6): 87, 74 and 34 patients received 1, 2, or 2+ lines, respectively, whereas 22 patients were
chemotherapy-naïve (Ch-N). Baseline characteristics of patients were well-balanced among the groups, except for EGOG
performance status core of 0 among the Ch-N patients that almost doubled that in the pretreated patients. Predominant
histological STS subtypes were leiomyosarcoma (41.9%), liposarcoma (23.5%) with similar percentages in Ch-N and
patients pretreated with 1 line. The patients in Ch-N group had longer time of response as the median number of cycles
they received (12 cycles) doubled those observed in pretreated patients with 1, 2, or 2+ lines (6, 7 and 5 cycles) and with
greater percent of patients on treatment for more >1 year (Ch-N 22.7% vs. 5.7%, 16.2%, 2.9%) (Table 1). With 166 PFS
events recorded, median PFS was 5.5 months (95% CI: 4.8-7.1 months) as assessed by RECIST (n=178), Choi (n=6) or
clinically (n=59). A clear trend towards shorter PFS in patients who received more extensive prior treatment was observed
(median PFS: 10.4, 5.9, 5.3, 4.4 months) (Figure 1). Trabectedin was generally well tolerated. Spontaneously reported
adverse events were similar across treatment lines and consistent with the known profile of trabectedin.
Conclusions: Trabectedin efficacy can be optimized when it is administered earlier allowing patients to
benefit from a long-term treatment, hence, to get longer disease control with respect to patients who
are treated later in the course of their disease.
Angiogenesis inhibitors
Role of VEGF-2 and PDGFR signalling in tumour
angiogenesis1–4
PDGF
VEGF
PDGFR
Cell
membrane
VEGFR-2
P
P P
P
P P
P P
PI3K
FAK
PLC
Erk
AKT
Paxillin
PKC
Proliferation
Survival
Migration
Ras
Raf
Permeability
Vascular tone
1. Hamberg P et al. Oncologist 2010;15:539; 2. Faivre S et al. Nat Rev Drug Discov 2007;6:734;
3. Andrae J et al. Genes Dev 2008;22:1276; 4. Sonpavde G et al. Expert Opin Investig Drugs 2008;17:253
59
Expression of VEGF is increased in soft tissue sarcoma
VEGF expression is observed in multiple STS subtypes1
Serum VEGF levels are elevated compared with controls2–6
Increased serum VEGF levels associated with STS subtypes2
1. Potti A et al. J Cancer Res Clin Oncol 2004;130:52; 2. Yoon SS et al. J Surg Res 2006;135:282; 3. Yoon SS et al. Ann Oncol 2004;15:1261; 4. Graeven U et al. J
60
Cancer Res Clin Oncol 1999;125:577; 5. Feldman A et al. Cancer 2001;91:1525; 6. Hayes AJ et al. Br J Surg 2004;91:242
VEGF expression is correlated with higher
tumour grade

VEGF overexpression by STS cells
leads to increased endothelial cell
proliferation, migration and
chemoresistance in vitro7
1000
500
0
Grade 3

1500
Grade 2

Benign lesions: 233 pg/ml
Grade 2: 413 pg/ml; p=0.007
Grade 3: 467 pg/ml; p=0.003
2000
Grade 1

2500
Benign
Median pre-treatment serum
VEGF concentration significantly
elevated in patients with STS:4
3000
Healthy
volunteers

Serum VEGF levels are
correlated with tumour grade4
Increased VEGF expression has
been associated with higher
tumour grade in a number of
studies in STS1–6
Serum VEGF (pg/ml)

1. Graeven U et al. J Cancer Res Clin Oncol 1999;125:577 2. Pakos EE et al. Anticancer Res 2005;25:3591; 3. Yudoh K et al. Br J Cancer
2001;84:1610; 4. Hayes AJ et al. Br J Surg 2004;91:242; 5. Chao C et al. Ann Surg Oncol 2001;8:260; 6. Iyoda A et al. Ann Thorac Surg
61
2001;71:1635; 7. Zhang L et al. Cancer Res 2006;66:8770
VEGF expression is associated with decreased
survival in soft tissue sarcoma

Increased VEGF expression has been correlated with decreased survival in a
number of studies in STS1–5

In one study, however, in patients with STS, VEGF expression was correlated with
tumour grade but not survival6
Median survival is significantly decreased in patients with VEGF-positive leiomyosarcoma1
STS type
Median survival (months)
p-value
VEGF+
VEGF–
Dermatofibrosarcoma (n=44)
72
50
0.29
Malignant fibrous histiocytoma (n=50)
14
23
0.30
Leiomyosarcoma (n=36)
8
30
0.01
Overall (n=273)
31
45
0.17
Patients diagnosed with STS between 1986 and 2001 (n=273)
*VEGF expression assessed by percentage of immunoreactive cells: >10% of the cells staining was graded as
positive. No detectable staining or <10% of cells staining was graded as negative
1. Potti A et al. J Cancer Res Clin Oncol 2004;130:52; 2. Yudoh K et al. Br J Cancer 2001;84:1610; 3. Iyoda A et al.
Ann Thorac Surg 2001;71:1635; 4. Kilvaer T et al. PLoS One 2010;5:e15368; 5. Potti A et al. Anticancer Res 2004;24:3339; 6. Chao C et
62
al. Ann Surg Oncol 2001;8:260
Role of PDGF/PDGFR in soft tissue sarcoma
PDGF-B is expressed in the majority of STS
tumours and expression is correlated with
higher tumour grade and increased cell
proliferation1

PDGFR-β is also expressed in STS1

PDGFR-α expression is upregulated in STS2

PDGF/PDGFR expression has also been
correlated with decreased survival3,4


Survival is associated with
PDGF-B expression in patients with
wide resection margins3
In patients with STS and wide resection margins
(n=108), high expression of PDGF-B (p=0.007) and
co-expression of PDGF-B and PDGFR-α (p=0.001)
were independent prognostic markers for
disease-specific survival3
In patients with rhabdomyosarcoma (n=89), high
PDGFR expression was associated with decreased
survival4
1
Disease-specific survival

p=0.007
Low expression, n=32
0.8
High expression, n=74
0.6
0.4
0.2
0
0
20
40
60
80
Survival (months)
100
120
1. Wang J et al. Cancer Res 1994;54:560; 2. Yoon SS et al. J Surg Res 2006;135:282; 3. Kilvaer T et al. Sarcoma 2010; 2010;751304; 4.
Blandford MC et al. Pediatr Blood Cancer 2006;46:329
63
Pazopanib
 Pazopanib
is an oral
angiogenesis
inhibitor
targeting
VEGFR,
PDGFR and c-Kit
 Binds to the cytoplasmic kinase
domain of
VEGFR-1, -2 and -3,
PDGFR-α and -β, and c-Kit1
 VEGFR regulates angiogenesis2
 PDGFR regulates angiogenesis
and proliferation of some tumour
cells3,4
 c-Kit regulates cellular
proliferation, survival, and
metastasis5
 Monohydrochloride salt
Pazopanib has exhibited minimal
in vitro inhibition of Flt-3 (involved in the development
of haematopoietic
stem cells)1
1.
2.
3.
4.
5.
Kumar et al. Mol Cancer Ther 2007;6:2012–21.
Kerbel. N Engl J Med 2008;358:2039–49.
Yu et al. J Biochem Mol Biol 2003;36:49–59.
Homsi and Daud. Cancer Control 2007;14:285–94.
Demetri. Semin Oncol 2001;28(5 Suppl 17):19–26.
Phase I trial of pazopanib in patients with advanced solid
tumours1

Open-label, non-randomized, dose-finding trial of pazopanib in patients with
advanced-stage, refractory solid tumours

Sequential dose-escalating cohorts (dose-escalation phase, n=43; dose expansion
phase, n=20) receiving pazopanib 50 mg three times weekly to 2000 mg once daily
and 300 mg to 400 mg twice daily


Three patients had partial response (two confirmed, one unconfirmed) and 14 patients had
stable disease ≥6 months
Monotherapy dose of 800 mg once daily was selected for further trials
 Mean
trough
concentration
of ≥15 had
μg/ml
(34 μmol/l)
at 800 mg once daily
Four patients
withtarget
sarcoma
treated
with pazopanib
stable
diseaseachieved
≥6 months
Subtype
Starting dose (mg)
Final dose (mg)
Duration of stable
disease (months)
Leiomyosarcoma
50 once daily
800 once daily
9.0
Chondrosarcoma
400 once daily
800 once daily
7.6
GIST
600 once daily
800 once daily
15.8
Chondrosarcoma
2000 once daily
800 once daily
19.8
GIST, gastrointestinal stromal tumour
1. Hurwitz H et al. Clin Cancer Res 2009;15:4220
65
66
Phase II EORTC study 62043 (VEG20002):
study design1
Treatment phase
Stage 1
(n=17)
C
O
N
SE
N
T
Adipocytic tumours
Verify
eligibility
≤2 weeks
(n=17)
Synovial sarcoma
(n=17)
Other STS
(n=17)
Stop if ≤3 of 17 subjects in stage
I are alive and progression-free
at Week 12
Leiomyosarcoma
Futility
analysis
Follow-up
Stage 2
Leiomyosarcoma
(additional n=~20)
Adipocytic tumours
(additional n=~20)
Synovial sarcoma
Follow-up
for PD every
12 weeks
(additional n=~20)
Follow-up
for survival
every
3 months
Other STS
(additional n=~20)
WD due to AE
Treatment discontinued
in either stage when
patients:
Experience PD
Death on treatment
End of study
WD consent
•
Phase II trial of pazopanib in relapsed or refractory STS
– Pazopanib 800 mg was administered orally, once daily
– The primary endpoint was progression-free rate at 12 weeks (PFR12)
AE, adverse event; EORTC, European Organisation for Research and Treatment of Cancer ; PD, progressive disease; PFS, progression-free survival; STS,
soft tissue sarcoma; WD, withdraw
1. Sleijfer S et al. J Clin Oncol 2009;27:3126
67
Phase II EORTC study 62043 (VEG20002):
progression-free survival and overall survival1
Overall survival
100
100
90
90
Adipocytic sarcomas
Leiomyosarcomas
Synovial sarcomas
80
80
Other sarcomas
Overall survival (%)
Progression-free survival (%)
Progression-free survival
70
60
50
40
30
70
60
50
40
30
20
20
10
10
0
0
0
3
6
9
12
15
18
Time (months)
1. Sleijfer S et al. J Clin Oncol 2009;27:3126
21
24
27
0
3
6
9
12
15
18
21
24
27
Time (months)
68
Phase II EORTC study 62043 (VEG20002):
tumour responses1
Leiomyosarcoma
(n=41)
Adipocytic
sarcoma (n=19)
Synovial
sarcoma
(n=37)
Other sarcoma
types (n=41)
Partial response, n
1
0
4
1
Stable disease, n
17
5
14
15
Progressive disease, n
21
13
14
23
Early death, n
1
1
3
2
Not evaluable, n
1
Parameter
1
Clinical progressive disease, n
PFS rate at 12 weeks, n/N (%)
1
18/41
(43.9)
5/19
(26.3)
18/37
(48.6)
16/41
(39.0)
PFS, progression-free survival
CT scan of a patient with leiomyosarcoma with partial response
Baseline
1.Sleijfer S et al. J Clin Oncol 2009;27:3126
After
3 months of
pazopanib
treatment
69
The PALETTE study
(PAzopanib expLorEd in sofT-Tissue
sarcoma
A phasE III study) 1
An EORTC STBSG and GlaxoSmithKline global network study (EORTC 62072; VEG110727)
1. Van Der Graaf W et al. Published on line May 16 2012. www.thelancet.com
70
Phase III Study Design
N= 369
R
A
N
D
O
M
I
S
E
Pazopanib*(800mg QD)
10
Endpoint
20
Endpoints
(N = 246)
2:1
PFS
(RECIST v1.0)
Matching Placebo
(N = 123)
Followed for
survival
* Until disease progression, unacceptable toxicity,
withdrawal of consent for any reason, or death
Van Der Graaf W et al. Published on line May 16 2012. www.thelancet.com
OS
ORR
QoL
Safety
Stratification factors
 Performance status
(0 vs 1)
 Number of prior lines of
systemic therapy for
advanced disease
(0/1 vs 2+)
Disease assessment
at week 4-8-12-20 and
at 8 week intervals
thereafter
Inclusion Criteria Histology
 Included:
•
Fibroblastic
•
MPNST
•
Fibrohistiocytic
•
NOS
•
Leiomyosarcoma
•
Vascular STS
•
Synovial sarcoma
•
Malignant glomus tumors
 Excluded:
•
Adipocytic sarcoma
•
DFSP
•
Osteosarcoma
•
Mixed mesodermal uterine tumor
•
Ewing sarcoma/PNET
•
GIST
•
Chondrosarcoma
•
Mesothelioma
•
Inflammatory myofibroblastic sarcoma
•
Non alveolar and non pleiomophic rhabdomyosarcoma
Van Der Graaf W et al. Published on line May 16 2012. www.thelancet.com
Progression Free Survival1
1. Van Der Graaf W et al. Published on line May 16 2012. www.thelancet.com
73
Overall Survival1
1. Van Der Graaf W et al. Published on line May 16 2012. www.thelancet.com
74
PALETTE: SAFETY DATA
PALETTE: newly identified serious adverse events1
SAEs with a higher incidence in the pazopanib-treated aSTS population than in
the pazopanib-treated aRCC population
On-therapy and
post-therapy
adverse events
Myocardial
dysfunction*
Venous
thromboembolic
†
events
Pneumothorax
Placebo
(n=123)
Any
grade
6 (5%)
Grade 3
Pazopanib
(n=240)
Any
grade
21 (9%)
Grade
3
3 (1%)
Grade 4
–
Grade
4
–
3 (2%)
1 (<1%)
2 (1%)
13 (5%)
5 (2%)
1 (<1%)
–
–
–
8 (3%)
–
1 (<1%)
1 (<1%)
*Grouping of MedDRA terms, including left ventricular dysfunction, cardiac failure, restrictive
cardiomyopathy and
pulmonary oedema
†Fatal pulmonary embolus occurred in two of 240 patients treated with pazopanib
Dati elaborati da testo
1. Van Der Graaf W et al. Published on line May 16 2012. www.thelancet.com
76
Conclusions
 Pazopanib demonstrated a statically significant increase in PFS
compared to placebo1
 PFS improved in patients in all age, for most histological subtypes
(leiomyosarcoma, synovial and others) 1
 Pazopanib is an active drug for pts with non adipocytic soft tissue
sarcoma. 1
“....After the breackthroughs of Imatinib and Sunitinib for GIST,
Pazopanib is the FIRST active oral agent for pts with NON GIST
and NON LIPO aSTS and is a eaningful addition to the treatment
armamentarium for pts with the rare group of tumors.” 1
1. Van Der Graaf W et al. Published on line May 16 2012. www.thelancet.com
77
Angiogenesis inhibitors
Istotipi “frequenti”: Aggiornamento protocolli
A Phase II study (TRAVELL) on trabectedin in advanced
retroperitoneal leiomyosarcoma and well
differentiated/dedifferentiated liposarcoma
Patients with previously treated retroperitoneal
leiomyosarcoma and well
differentiated/dedifferientiated liposarcoma
unamenable to surgery or amenable but the addition
of a medical treatment is clinically felt advisable
Istotipi “frequenti”: Aggiornamento protocolli
A Phase II study (TRAVELL) on trabectedin in advanced
retroperitoneal leiomyosarcoma and well
differentiated/dedifferentiated liposarcoma
Main inclusion criteria
 Persistent or locally relapsed and/or metastatic disease (in case of local disease,
surgery may be technically feasible or not, but the clinical judgment must be that a
medical therapy is indicated)
 Pathology specimens available for centralized review
(Department of Pathology of Treviso-Dr. Dei Tos)
 ECOG PS <=2
 One or more previous systemic treatments employing anthracyclines and
ifosfamide (unless one or both are clinically contraindicated)
Main exclusion criteria
 Prior exposure to trabectedin
Istotipi “frequenti”: Aggiornamento protocolli
A Phase II study (TRAVELL) on trabectedin in advanced
retroperitoneal leiomyosarcoma and well
differentiated/dedifferentiated liposarcoma
 Phase II, multicenter, single arm
Enrolling centres: about 20 centres ISG
of 3-4 years
 Primary end-point:
Growth modulation rate =
80 patients over a period
PFS to T
---------------------TTP to previous CT
 Secondary end-points: Objective response, progression free survival, and
objective response in the two eligible histological types, PFS in pts who
undergo surgery and those who do not, pathological tumor response in pts
undergoing surgery, safety profile
Istotipi “frequenti”: Aggiornamento protocolli
A Phase II study (TRAVELL) on trabectedin in advanced
retroperitoneal leiomyosarcoma and well
differentiated/dedifferentiated liposarcoma
 Trabectedin 1,5 mg/mq or 1,3 mg/mq according to Investigator’s
choice (with a top-dose of 2,6 total mg per cycle)
 CT scan will be performed every 3 cycles
Translational Study
About 15-20 patient to asses tumor biological features associated to different
response patterns to trabectedin
All patients who undergone surgery after trabectedin treatment
Istotipi “frequenti”: Aggiornamento protocolli
STRASS Study: A phase III randomized study of
preoperative radiotherapy plus surgery versus surgery
alone for patients with Retroperitoneal sarcoma (RPS)
 Primary soft tissue sarcoma of retroperitoneal or infra-peritoneal
spaces of pelvis, unifocal disease and not previously treated
 259 pts will be randomized over a period of 39 months
 Primary endpoint: abdominal recurrence free survival (local relapse,
R2 surgery, PD or non-resectable disease during RT, peritoneal
sarcomatosis)
Istotipi “frequenti”: Aggiornamento protocolli
Investigational arm : preoperative RT 50.4 Gy (28 daily fractions) + Large en-bloc
curative-intent surgery
Control arm: Large en-bloc curative-intent surgery alone
GIST
Chemotherapy, Radiation, and
Surgery in GIST
Surgery1,2

Principal treatment for resectable primary GIST
Chemotherapy1,3-5



Ineffective in sarcomas
Response limited: ~5%
Survival: no impact
1. DeMatteo RP et al. Hum Pathol. 2002;33:466-477.
2. Pierie JP et al. Arch Surg. 2001;136:383-389.
3. Hatch KF et al. World J Surg. 2000;24:437-443.
Radiation1,2



Results in injury to adjacent organs
Tumors exhibit radioresistance
Possible therapeutic role in rectal
tumors
4. Rossi CR et al. Int J Cancer. 2003;107:171-176.
5. Demetri G et al. J Natl Compr Canc Netw. 2004;2
(suppl 1):S1-S26.
GIST: Current Treatment Options
Surgery
Treatment of choice for localized
primary resectable GIST1,2
1. Demetri G et al. J Natl Compr Canc Netw. 2004;2(suppl 1):S1-S26.
2. Blay JY et al. Ann Oncol. 2005;16:566-578.
Imatinib
First-line treatment of
malignant unresectable or
metastatic GIST1,2
Treatment Algorithm for Patients With Primary
Metastatic or Recurrent GIST
Primary disease
No Metastasis
Recurrent disease
Surgery feasible
or unresectable
(Neoadjuvant)
Imatinib
Surgery
Nilotinib
Postoperative
imatinib (adjuvant)
Response or
stable disease
Surgery ??
Adapted from Sanne M et al Cancer 2005;104:1781-8.
Progression
Sunitinib
or surgery ??
Clinical trials:
Imatinib + nilotinib
Imatinib + other
Risk of Aggressive Tumor Behavior
All GISTs should be considered to have potential for
malignant behavior1,2
Size
(cm)
Mitotic Count
(HPF)
Very low risk
<2
<5/50
Low risk
2-5
<5/50
Intermediate risk
<5
5-10
6-10/50
<5/50
>5
>10
Any size
>5/50
Any mitotic rate
>10/50
High risk
HPF, high-power fields.
1. Fletcher CD et al. Hum Pathol. 2002;33:459-465.
2. Miettinen M et al. Hum Pathol. 2002;33:478-483.
Classificazione del rischio
cm
M/50HPF
gastric
jejunal/
ileal
duodenal
rectal
1
<2
<5
0
none
0
none
0
none
0
none
2
>2<5
<5
1.9%
very low
4.3%
low
8.3%
low
8.5%
low
3a
>5<10
<5
3.6%
low
24%
moderate
3b
>10
<5
12%
moderate
52%
high
34%
high
57%
high
4
<2
>5
0
50%
5
>2<5
>5
16%
moderate
73%
high
6a
>5<10
>5
55%, high
85%, high
6b
>10
>5
86%
high
90%
high
54%
high
50%
high
52%
high
86%
high
71%
high
Regorafenib nella terapia per i GIST: ora
disponibile tramite il SSN
Siamo lieti di comunicare che è stata pubblicata la DETERMINA 24
luglio 2015 con la quale l’Agenzia Italiana del Farmaco AIFA ha
autorizzato la classificazione e la rimborsabilità di Regorafenib
(Stivarga) nell’uso dei GIST e dei Carcinomi del Colon Retto.
Con Determina n. 1016 AIFA ha autorizzato il nuovo medicinale per
il trattamento dei pazienti adulti affetti
da tumori stromali gastrointestinali (gastrointestinal stromal tumors,
GIST) non resecabili, dopo progressione di malattia o intolleranti
al trattamento precedente con imatinib e sunitinib.
STUDI APPROVATI NON ANCORA APERTI PER IL RECLUTAMENTO
Masitinib Studio prospettico di Fase III , multicentrico, randomizzato, controllato con placebo per confrontare l'efficacia e la sicurezza di masitinib vs placebo in pazienti con GIST primario localizzato dopo completa
chirurgia e con alto rischio di recidiva.
Sponsor AB Science
Numero ID AB 12004
Arruolamento stimato n. 330
Inizio Gennaio 2014
Compimento Dicembre 2016
https://clinicaltrials.gov/ct2/show/NCT02009423?term=NCT02009423&rank=1
SARC 029 Trametinib e Pazopanib in pazienti con GIST. Studio di Fase II di Trametinib in combinazione con Pazopanib in pazienti con GIST avanzato refrattari o intolleranti ad almeno imatinib e sunitinib. Studio
non randomizzato, in aperto per valutare efficacia e sicurezza.
Sponsor: Sarcoma Alliance for Research through Collaboration.
Collaboratori GlaxoSmithKline
Arruolamento stimato n. 45
Inizio Marzo 2015. Compimento Marzo 2018
Contatti: SARC OFFICE 734-930-7600 [email protected]
https://clinicaltrials.gov/ct2/show/NCT02342600?term=gastrointestinal+stromal+tumor&rank=54
Studio di fase II di BB1503 in pazienti adulti con tumore stromale gastrointestinale avanzato.
E' uno studio in aperto, multicentrico, per pazienti che hanno esaurito le opzioni terapeutiche standard attualmente approvate.
Il farmaco è' somministrato per via orale, ogni giorno alla dose di 300 mg una volta al giorno.
ID N. BB1503-205c
Sponsor Boston Biomedical Inc
Arruolamento stimato n. 30
Inizio Gennaio 2015
Compimento Gennaio 2016
https://clinicaltrials.gov/ct2/show/NCT02232620?term=gastrointestinal+stromal+tumor&recr=Open&no_unk=Y&rank=10
CABOGIST Studio di fase II multicentrico, muultinazionale a braccio singolo per valutare la sicurezza e l'attività di cabozantinib in pazienti con GIST metastatico che hanno avuto progressione durante terapia
neoadiuvante, adiuvante o terapia palliativa con imatinib e sunitinib.
Sponsor EORTC European Organisation for Research and Treatment of Cancer
N. ID dello studio EORTC-1317, 2014-000501-13
N. stimato dei pazienti arruolati 50
Inizio Luglio 2015
Completamento stimato Gennaio 2017
https://clinicaltrials.gov/ct2/show/NCT02216578?term=CABOGIST&rank=1
Studio di Fase I di BLU-285 in pazienti con tumore stromale gastrointestinale ed altri tumori solidi recidivati o refrattari.
Sponsor: Blueprint Medicines Corporatio.
E' uno studio di fase I open label, studio di aumento della dose, per valutare la sicurezza, la tollerabilità, l'efficacia, la farmacodinamica, la farmacocinetica e la preliminare attività antitumorale di BLU 285
somministrata oralmente in pazienti con GIST inoperabile o altri tumori solidi recidivati o refrattari.
Lo studio consiste di due parti, una parte di aumento della dose ed una parte di espansione. Nella parte 1 saranno arruolati pazienti con GIST inoperabile, con malattia che ha avuto progressione dopo imatinib e
almeno uno dei seguenti agenti: sunitinib, regorafenib, sorafenib, dasatinib,pazopanib o altro farmaco sperimentale inibitore di KIT, o malattia con mutazione D842 nel gene PDGFRA.
Arruolamento stimato, n.60
Inizio Agosto 2015; completamento maggio 2019
Centri di sperimentazione 3 USA (Boston, Portland, Philadelphia)
https://www.clinicaltrials.gov/ct2/show/NCT02508532?term=gastrointestinal+stromal+tumor&rank=75
Therapeutic Drug Monitoring
“process of assessing concentration of the drug in biological
fluids such that it is maintained within the therapeutic
range”
Drugs Requiring TDM
- Narrow therapeutic range
- Significant pharmacokinetic variability (ADME)
- Drugs which show therapeutic as well as ADR based on their
concentrations
- Well established relationship between PK exposure and clinical
response
- Drugs which follow saturation metabolism
- Availability of cost effective drug assay
IMATINIB
PHARMACOKIENTICS INTERPATIENTS VARIABILITY
-
Dosage regimen and Duration of therapy
-
Patient characteristics
-
Alteration in elimination of drugs
-
Alteration in Protein binding
-
Pathological characteristics
-
Drug interactions
-
Diet, smoking and alcohol consumption
DISTRIBUTION OF IMATINIB CMIN
Cmin is associated to clinical benefit
Cmin cutoff 1100 ng/mL
OUR RESULTS
titolo
Most of the patients
present C trough
within the optimal
range however some
patients are under
dosed