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Nuovi farmaci per terapia in uso clinico: Ra-223
Ettore Seregni
Terapia
Terapia Medico-Nucleare
Medico-Nucleare ed
ed Endocrinologia
Endocrinologia
E.S.
Ra-223: caratteristiche
 Il Radio-223:
calcio-mimetico
20
Tavola periodica
Ca degli elementi
idrogeno
metalli alcalini
metalli alcalino terrosi
metalli di transizione
38
Sr
 Si lega alla componente
minerale nelle sedi di
aumentato turn-over
osseo
56
Ba
88
Ra
E.S.
metalli
nonmetalli
gas nobili
metalli alcalino-terrosi
Ra-223: schema di decadimento
223Ra
11.43 d
Dell'energia di decadimento totale:
α
Il 93.5% viene emesso come particelle α
219Rn
3.96 s
α
< 4% viene emesso come particelle β< 2% viene emesso come raggi γ o raggi X
E.S.
215Po
1.78 ms
α
211Pb
36.1 min
β−
β− 211Bi
2.17 min
α
(99.72%)
207TI
4.77 min
(0.28%)
211Po
516 ms
α
β−
207Pb
stable
β-emitters
• Low-LET β-radiation  single-strand DNA breaks
• Single-strand breaks: easily repaired
• Single-strand breaks  less likely to induce cell death
α-emitters
• High-LET α-particles  double-strand DNA breaks
• Double-strand breaks: difficult to repair
• Failure to repair  to apoptosis
Range of alpha particle
Range of beta particle
(2-10 cell diameters)
(10-1000 cell diameters)
Marrow
Marrow
Radium-223
Bone
E.S.
Bone
Beta emitter
E.S.
E.S.
E.S.
E.S.
ALSYMPCA: chemotherapy post Ra-223: subgroup analysis
•
147 Pts. in the ALSYMPCA study went on to receive chemotherapy, after completing study
drug treatment
•
93 of pts. had received radium-223
•
The most common chemotherapeutic agents administered after study drug treatment were
docetaxel (n = 105), mitoxantrone (n = 23), and cyclophosphamide (n = 19)
Chemotherapy After Study Drug in ALSYMPCA
Pts treated with CT after study drug (n)
E.S.
Radium 223
(n = 614)
Placebo
(n = 307)
93
54
Sartor O, et al. Presented at ESMO 2012. Poster 936P
ALSYMPCA: chemotherapy post Ra-223: subgroup analysis
• In patients receiving chemotherapy after the last dose of study drug (n = 147),
median values of hemoglobin, neutrophils, and platelets were similar for the
radium-223 vs placebo group from baseline to month 12
• Administering chemotherapy after radium-223 had no deleterious effect on
patient OS
• Hematologic safety profiles for patients receiving chemotherapy after
radium-223 were similar to those for patients receiving chemotherapy after
placebo
E.S.
Sartor O, et al. Presented at ESMO 2012. Poster 936P
N° Pazienti: 25
Solo 223-Ra: 11
223-Ra + abiraterone: 6
223-Ra + enzalutamide: 8
Inibizione 17α-idrossilasi/C17,20-liasi (CYP17)
enzalutamide
Inibizione di AR
E.S.
Dan TD, Am J Oncol, 2015
Neutrophils
(x 106/L)
Hemoglobin
(g/L)
Platelet count
(x 109/L)
E.S.
Dan TD, Am J Oncol, 2015
3-year safety follow-up of radium-223 dichloride (Ra-223) in patients with
castration-resistant prostate cancer (CRPC) and symptomatic bone metastases
from ALSYMPCA.
Ra-223
n = 600
All grades
Ra-223
n = 600
Grades 3/4
Pbo
n = 301
All grades
Pbo
n = 301
Grades 3/4
187 (31)
79 (13)
93 (31)
39 (13)
30 (5)
13 (2)
3 (1)
2 (1)
69 (12)
39 (7)
17 (6)
6 (2)
Bone pain
310 (52)
132 (22)
192 (64)
79 (26)
Diarrhea
154 (26)
8 (1)
45 (15)
6 (2)
Nausea
215 (36)
10 (2)
102 (34)
6 (2)
Vomiting
116 (19)
10 (2)
41 (14)
7 (2)
Constipation
109 (18)
7 (1)
64 (21)
4 (1)
Fatigue
160 (27)
27 (5)
79 (26)
18 (6)
Pts with tx-emergent
AEs of interest, n (%)
Hematologic
Anemia
Neutropenia
Thrombocytopenia
Non hematologic
E.S.
J Clin Oncol 33, 2015 (suppl 7; abstr 195)
3-year safety follow-up of radium-223 dichloride (Ra-223) in patients with
castration-resistant prostate cancer (CRPC) and symptomatic bone metastases
from ALSYMPCA.
E.S.
J Clin Oncol 33, 2015 (suppl 7; abstr 195)
External beam radiation therapy (EBRT) use and safety with radium-223 dichloride
(Ra-223) in patients (pts) with castration-resistant prostate cancer (CRPC) and
symptomatic bone metastases from the ALSYMPCA trial
cEBRT
cEBRT
No cEBRT
No cEBRT
Ra-223
n = 227
Pbo
n = 140
Ra-223
n = 373
Pbo
n = 161
77 (34)
51 (36)
110 (30)
41 (26)
14 (6)
1 (1)
16 (4)
2 (1)
27 (12)
8 (6)
42 (11)
9 (6)
Diarrhea
71 (31)
26 (19)
80 (21)
19 (12)
Nausea
98 (43)
61 (44)
115 (31)
43 (27)
Vomiting
56 (25)
26 (19)
55 (15)
15 (9)
Constipation
54 (24)
35 (25)
54 (15)
29 (18)
Patients with AEs, n (%)
Hematologic
Anemia
Neutropenia
Thrombocytopenia
Nonhematologic
E.S.
J Clin Oncol 33, 2015 (suppl 7; abstr 182)
Effect of radium-223 dichloride (Ra-223) on pain from US EAP
Radium-223 was associated with meaningful pain relief in 42% of pts, whereas 28% had
worse pain and 18% no change.
E.S.
J Clin Oncol 33, 2015 (suppl 7; abstr 160)
Prior and concurrent use of abiraterone and enzalutamide with
Ra-223 in an expanded access setting
Abi
N = 35
n
Abi
N = 35
%
Enza
N = 25
n
Enza
N = 25
%
70
Overall
N = 184
n
Overall
N = 184
%
Age, median, yrs
68
Race, white
31
Weight, median, kg
87
ECOG, ≤ 1
35
100
24
96
165
90
Total ALP ≥ 220 U/L
8
23
8
32
56
30
Current bisphosphonate,
yes
6
17
6
24
18
10
Prior docetaxel, yes
14
40
15
60
109
59
Pts receiving all 6
injections
20
57
15
60
81
44
89
23
70
92
90
169
92
86
Conclusions: In this EAP, Ra-223 concurrently administered with either
abiraterone or enzalutamide was safe and well tolerated
E.S.
J Clin Oncol 33, 2015 (suppl 7; abstr 253)
Radium-223 dichloride (Ra-223) in U.S. expanded access program (EAP)
Age, yrs
Hemoglobin, g/dl
tALP, U/L
PSA, ug/L
Time since diagnosis, yrs
EAP N=184
ALSYMPCA N=600
70
12
154
129.5
6.5
71
12.2
211
146
4.9
59
18
65
33
48
31
5
44
14
57
35
19
5
63
56
Prior therapy/procedures, %
docetaxel
carbazitaxel
abiraterone
enzalutamide
radiotherapy to prostate
prostatectomy
Median no. injections
% 6 injections
Delays/interruptions (%)
E.S.
J Clin Oncol 33, 2015 (suppl 7; abstr 247)
Radium-223 dichloride (Ra-223) in U.S. expanded access program (EAP)
E.S.
J Clin Oncol 33, 2015 (suppl 7; abstr 247)
Effects of radium-223 dichloride (Ra-223) with docetaxel (D) versus D on PSA and bALP in
patients with castration-resistant prostate cancer (CRPC) and bone metastases
PSA
bALP
bALP
Ra-223 + D = 33
D = 13
Ra-223 + D = 23
D = 11
3 (9)
4 (31)
0 (0)
0 (0)
< 30%
4 (12)
1 (8)
0 (0)
0 (0)
≥ 30%
26 (79)
8 (62)
23 (100)
11 (100)
> 50%
21 (64)
7 (54)
21 (91)
9 (82)
> 80%
10 (30)
4 (31)
9 (39)
2 (18)
N/A
N/A
21 (91)
6 (55)
PSA
Any increase
Decreases
Normalization
E.S.
J Clin Oncol 33, 2015 (suppl 7; abstr 202)
Protocol 16506: A re-treatment safety study of radium-223 dichloride in subjects with
castration-resistant prostate cancer with bone metastases who received an initial course of
six doses of radium-223 dichloride 50 kBq/kg every four weeks
E.S.
Protocol 15396: A phase III randomized, double blind, placebo-controlled trial of
radium-223
dichloride
in
combination
with
abiraterone
acetate
and
prednisone/prednisolone in the treatment of asymptomatic or midly symptomatic
chemoterapy-naive subjects with bone predominant metastatic castration-resistant
prostate cancer
E.S.
A phase IIa, nonrandomized study of radium-223 dichloride
in advanced breast cancer patients with bone-dominant disease
E.S.
Coleman R et al. Breast Cancer Res Treat (2014) 145:411–418
A phase IIa, nonrandomized study of radium-223 dichloride
in advanced breast cancer patients with bone-dominant disease
At weeks 9
At weeks 17
Coleman R et al. Breast Cancer Res Treat (2014) 145:411–418
E.S.
A phase IIa, nonrandomized study of radium-223 dichloride
in advanced breast cancer patients with bone-dominant disease
Coleman R et al. Breast Cancer Res Treat (2014) 145:411–418
E.S.
Ra-223: approvazione EMEA
Indicazioni terapeutiche:
e' indicato per il trattamento di soggetti adulti affetti da
carcinoma prostatico resistente alla castrazione, con metastasi
ossee sintomatiche e senza metastasi viscerali note.
E.S.
Decreto Legislativo 26 maggio 2000, n. 187
"Attuazione della direttiva 97/43/Euratom in materia di protezione sanitaria delle
persone contro i pericoli delle radiazioni ionizzanti connesse ad esposizioni
mediche"
ALLEGATO I (previsto dall’art.3, comma 8):
E.S.