6Î9Ô 98-104a 9Õ - pmda.go.jp · n o ^ 9 1 r i 1s2 Á9Ø2 1s4f5r(Â ] ... 0.75 3 17 9Ø18 19 0.90...
TRANSCRIPT
![Page 1: 6Î9Ô 98-104A 9Õ - pmda.go.jp · n O ^ 9 1 R I 1s2 Á9Ø2 1s4F5R(Â ] ... 0.75 3 17 9Ø18 19 0.90 6 20 9Ø21 22 23 24 25 1.08 3 26 9Ø27 28 1.30 3 29 9Ø30 31 1.56 12 32 9](https://reader031.vdocuments.us/reader031/viewer/2022022716/5c16e46109d3f263628cdb44/html5/thumbnails/1.jpg)
2.7.6 98-104A 47
2.7.6.2.2 98-104A 5.3.5.2.7
2.7.6.2.2.1
2.7.6.2.2-1
2.7.6.2.2-1
98-104AAghajanian C, Elliott PJ, Adams J, Soignet S, Spriggs DR. Phase I trial of the proteasome inhibitor PS-341 in advanced malignancy. Abstract 736. 36th Annual Meeting of the American Society of Clinical Oncology; May 2000; New Orleans, LA.
Aghajanian C, Soignet S, Dizon DS, Pezzulli S, A Daud, Spriggs D, et al. A Phase I Trial of the Novel Proteasome Inhibitor PS341 in Advanced Solid Tumor Malignancies. Abstract 338. 37th Annual Meeting of the American Society of Clinical Oncology; May 2001; San Francisco, CA.
Aghajanian C, Soignet S, Dizon DS, Pien CS, Adams J, Elliott PJ, et al. A Phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res. 2002 Aug;8(8):2505-11
2 2 1DLT MTD
2 2 1 20S
20Sin vitro TNF I B
1)2)183) Karnofsky 704) 14
8.0 g/dL 3,000 /mm3
1,500 /mm3
100,000 /mm3
SGOT AST N 2.5 NSGPT ALT N 2.5
1.8 mg/dL
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2.7.6 98-104A 48
50 mL/min 1.5 mg/dL
5) 50%6)
1) 22) 43) 44) 45)6)
7) 2
8)9)
10)11)212) X
13)
DLT MTD 3 6MTD 343
DLT 1 Grade4 Grade4Grade3 Grade3
MTD DLT 3 0 0% 6 1 17%
191 mL 0.5 mg 2 mL
2.5 mg 25 mg
1 0.13, 0.25, 0.40, 0.60, 0.75, 0.90, 1.08, 1.30, 1.56, 1.75, 1.85 1.95 mg/m2
0.13 1.56 mg/m2
1 1 2 2 1 4 8 11 103 1 2 CR PR SD
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2.7.6 98-104A 49
0.13 mg/m2 3 3 1DLT 0.25 mg/m2
3 1 DLT 36 2 DLT 1
MTD
141 Day1 4 8 11 Day12 21
1 Day1 24 Day26 2 Day1
4 8 11 Day12 21 11
20S
ITT Intent-To-Treat
KarnofskyX
MTD DLT90%
SAS ver. 8.02
11920
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2.7.6 98-104A 50
2.7.6.2.2.2
(1)
Memorial Sloan-Kettering Cancer Center MSKCC 43
9 2.7.6.2.2-2
2.7.6.2.2-2
(mg/m2)N
0.13 3 1 2 30.25 4 4 5 6 70.40 5 8 9 10 11 120.60 4 13 14 15 160.75 3 17 18 190.90 6 20 21 22 23 24 251.08 3 26 27 281.30 3 29 30 311.56 12 32 33 36
37 35 3438 39 40 41 42 43
DLT
0.13 1.30 mg/m2 DLT
3 0.25 0.40 0.60 0.90 mg/m2
3 3
1
1.56 mg/m2 3 1 DLT 33 Grade3
3 3 DLT
1.56 mg/m2 6
6 2 DLT 39 Grade3
42 Grade3 1.56 mg/m2 25% 3/12
DLT 1 1.30 mg/m2 MTD
2.7.6.2.2- 1 43 1
ITT
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2.7.6 98-104A 51
43
ITT
43
2.7.6.2.2- 1
(2)
2.7.6.2.2-3 2 1
2 4 4 56% 24/43 2
2
2 PD 84%
36/43 9% 4/43 5% 2/43
2% 1/43
2.7.6.2.2-3
(mg/m2)0.13 (n=3) n(%)
0.25 (n=4) n(%)
0.40 (n=5) n(%)
0.60 (n=4)n(%)
0.75 (n=3)n(%)
0.90 (n=6)n(%)
1.08 (n=3)n(%)
1.30 (n=3) n(%)
1.56 (n=12) n(%)
(n=43)n(%)
3(100) 4(100) 5(100) 4(100) 3(100) 6(100) 3(100) 3(100) 12(100) 43(100)
23(100) 3(75) 3(60) 1(25) 3(100) 5(83) 2(67) 1(33) 3(25) 24(56)
3(100) 4(100) 4(80) 3(75) 3(100) 6(100) 3(100) 2(67) 8(67) 36(84)
0 0 0 0 0 0 0 1(33) 3(25) 4(9) 0 0 1(20) 0 0 0 0 0 1(8) 2(5) 0 0 0 1(25) 0 0 0 0 0 1(2)
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2.7.6 98-104A 52
(3)
43 2.7.6.2.2-4 2.7.6.2.2-5
56% 24/43 79% 34/43
54 34 75 Karnofsky 80
70 90
19% 8/43
14% 6/43 9% 4/43 7% 3/43
5% 2/43 2% 1/43
5% 2/43 3.8
0.4 10.5
43 91% 39/43
3.7 3.0
42% 18/43
37% 16/43 23% 10/43
21% 9/43 Ro 31-7453 19% 8/43
28% 12/43
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2.7.6 98-104A 53
2.7
.6.2
.2-4
N=4
3
(m
g/m
2 )0.
13(n
=3)
0.25
(n=4
)0.
40(n
=5)
0.60
(n=4
)0.
75(n
=3)
0.90
(n=6
)1.
08(n
=3)
1.30
(n=3
)1.
56(n
=12)
(n=4
3)n
(%)
1 (3
3)
1 (2
5)
2 (4
0)
1 (2
5)
2 (6
7)
1 (1
7)
2 (6
7)
2 (6
7)
7 (5
8)
19 (4
4)
2 (6
7)
3 (7
5)
3 (6
0)
3 (7
5)
1 (3
3)
5 (8
3)
1 (3
3)
1 (3
3)
5 (4
2)
24 (5
6)
n (%
)
2
(67)
3
(75)
5
(100
) 4
(100
) 3
(100
) 5
(83)
1
(33)
3
(100
) 8
(67)
34
(79)
0
0 0
0 0
1 (1
7)
0 0
3 (2
5)
4 (9
) /
0
1 (2
5)
0 0
0 0
1 (3
3)
0 1
(8)
3 (7
) /
1
(33)
0
0 0
0 0
0 0
0 1
(2)
0 0
0 0
0 0
1 (3
3)
0 0
1 (2
) (
)
N
3
4 5
4 3
6 3
3 12
43
(
SD)
40 (4
.0)
48 (5
.4)
56 (1
4.3)
56
(16.
8)
66 (6
.5)
54 (1
1.4)
60
(13.
5)
62 (1
0.2)
52
(8.2
) 54
(11.
3)
40
48
57
55
66
53
60
64
50
53
36,4
4 42
,55
34,7
4 40
,75
60,7
3 38
,67
46,7
3 51
,71
40,6
4 34
,75
(kg
)
N
3
4 5
4 3
6 3
3 12
43
(
SD)
54 (4
.4)
59 (1
0.4)
61
(12.
0)
58 (1
0.0)
81
(23.
2)
89 (2
6.6)
67
(4.4
) 61
(15.
9)
76 (1
5.8)
70
(18.
7)
53
58
61
57
84
84
66
62
77
67
51,5
9 47
,72
47,7
8 49
,69
56,1
02
67,1
39
63,7
2 44
,76
56,1
12
44,1
39
(cm
)
N
3
4 5
4 3
6 3
3 11
42
(
SD)
159
(5.5
) 16
3 (7
.3)
164
(10.
8)16
6 (1
1.7)
178
(9.2
) 16
5 (8
.9)
174
(13.
9)16
5 (8
.1)
170
(9.1
) 16
7 (9
.9)
156
163
160
162
180
164
173
160
168
167
155,
165
154,
170
152,
177
157,
183
168,
186
156,
178
161,
189
160,
174
155,
186
152,
189
Kar
nofs
ky
N
3
4 5
4 3
6 3
3 12
43
(
SD)
80 (1
0.0)
83
(9.6
) 76
(8.9
) 78
(5.0
) 87
(5.8
) 83
(6.1
) 77
(2.9
) 78
(2.9
) 81
(7.6
) 80
(7.2
) 80
85
70
80
90
80
75
80
80
80
70
,90
70,9
0 70
,90
70,8
0 80
,90
75,9
0 75
,80
75,8
0 70
,90
70,9
0
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2.7.6 98-104A 54
2.7
.6.2
.2-5
N=4
3
(m
g/m
2 )0.
13(n
=3)
0.25
(n=4
)0.
40(n
=5)
0.60
(n=4
)0.
75(n
=3)
0.90
(n=6
)1.
08(n
=3)
1.30
(n=3
)1.
56(n
=12)
(n=4
3)n
(%)
0 1
(25)
0
1 (2
5)
0 0
0 1
(33)
5
(42)
8
(19)
0
1 (2
5)
0 1
(25)
0
0 1
(33)
0
3 (2
5)
6 (1
4)
1 (3
3)
0 0
0 0
0 1
(33)
1
(33)
1
(8)
4 (9
) 0
1 (2
5)
0 1
(25)
1
(33)
1
(17)
0
0 0
4 (9
) 0
0 2
(40)
0
0 1
(17)
0
1 (3
3)
0 4
(9)
0 0
0 1
(25)
1
(33)
2
(33)
0
0 0
4 (9
) 0
0 1
(20)
0
0 1
(17)
0
0 1
(8)
3 (7
) 0
0 1
(20)
0
0 1
(17)
0
0 0
2 (5
) 0
0 0
0 0
0 1
(33)
0
1 (8
) 2
(5)
0 1
(25)
1
(20)
0
0 0
0 0
0 2
(5)
1 (3
3)
0 0
0 0
0 0
0 0
1 (2
) 1
(33)
0
0 0
0 0
0 0
0 1
(2)
0 0
0 0
0 0
0 0
1 (8
) 1
(2)
0 0
0 0
1 (3
3)
0 0
0 0
1 (2
)
N
3
4 5
4 3
6 3
3 12
43
(
SD)
1.4
(0.8
1)2.
7 (2
.51)
5.6
(3.4
2)5.
8 (3
.56)
3.3
(2.7
6)4.
6 (3
.57)
2.3
(1.2
3)3.
5 (2
.82)
3.3
(2.5
8)3.
8 (2
.86)
1.
2 2.
0 4.
2 7.
0 2.
7 4.
0 1.
6 2.
8 2.
8 2.
8 0.
8,2.
3 0.
4,6.
3 1.
7,9.
4 0.
7,8.
5 1.
0,6.
4 0.
8,9.
8 1.
5,3.
7 1.
2,6.
6 1.
1,10
.5
0.4,
10.5
N
3
4 5
4 3
6 3
3 12
43
(
SD)
1.7
(1.1
5)1.
8 (0
.96)
5.4
(4.5
6)4.
8 (2
.22)
1.3
(0.5
8)3.
2 (1
.83)
4.7
(1.5
3)2.
7 (0
.58)
4.5
(2.1
1)3.
7 (2
.46)
1.
0 1.
5 4.
0 5.
0 1.
0 3.
0 5.
0 3.
0 4.
0 3.
0 1.
0,3.
0 1.
0,3.
0 2.
0,13
.0
2.0,
7.0
1.0,
2.0
1.0,
6.0
3.0,
6.0
2.0,
3.0
3.0,
10.0
1.
0,13
.0
n (%
)
1
(33)
0
4 (8
0)
1 (2
5)
2 (6
7)
2 (3
3)
1 (3
3)
1 (3
3)
6 (5
0)
18 (4
2)
1 (3
3)
1 (2
5)
3 (6
0)
1 (2
5)
0 0
3 (1
00)
0 7
(58)
16
(37)
0
1 (2
5)
2 (4
0)
0 0
2 (3
3)
1 (3
3)
1 (3
3)
3 (2
5)
10 (2
3)
1 (3
3)
0 4
(80)
0
0 1
(17)
0
0 4
(33)
10
(23)
0
1 (2
5)
0 0
0 0
3 (1
00)
0 5
(42)
9
(21)
R
O 3
1-74
53
0 0
1 (2
0)
2 (5
0)
1 (3
3)
1 (1
7)
0 0
3 (2
5)
8 (1
9)
n (%
) 3
(100
) 2
(50)
5
(100
) 4
(100
) 3
(100
) 5
(83)
3
(100
) 3
(100
) 11
(92)
39
(91)
n
(%)
2 (6
7)
0 2
(40)
0
0 0
1 (3
3)
1 (3
3)
6 (5
0)
12 (2
8)
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2.7.6 98-104A 55
(4)
1)
2.7.6.2.2-6
2.7.6.2.2-6
CR
4
PR 2 50%
4 50%
SD 2 50%
50% 50% 50%
PD 2 50%
50%
ITT 43 2.7.6.2.2-7 5% 2/43
2 1.30 mg/m2 31 1.30 mg/m2
16 SD
35 1.56 mg/m2 NSCLC PR
2 2 31
35
2.7.6.2.2-7 ITT N=43
(mg/m2)<0.4(n=7)n (%)
0.40 - 0.60 (n=9)n (%)
>0.60 - 1.00(n=9)n (%)
>1.00 - <1.50 (n=6)n (%)
1.50(n=12)n (%)
(n=43)n(%)
CR 0 0 0 0 0 0 PR 0 0 0 0 1 (8) 1 (2) SD 0 0 0 1 (17) 0 1 (2) PD 7 (100) 8 (89) 9 (100) 5 (83) 9 (75) 38 (88)
0 1 (11) 0 0 2 (17) 3 (7) CR PR SD PD
2)
36 1 1, 4, 8 11 20S
ChT:T 2.7.6.2.2-2 2.7.6.2.2-8
1 20S
20S 10%
2.7.6.2.2-9 20S 72 96
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2.7.6 98-104A 56
20S 72 96
0
10
20
30
40
50
60
70
80
90
100
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 252
(hr)
20S
(%
) 0.40 - 0.60 mg/m2
>0.60 - 1.00 mg/m2
>1.00 - <1.50 mg/m2
1.50 mg/m2
1 2 3 4
2.7.6.2.2-2 1 20S0.40 0.60 mg/m2 n=9, >0.60 1.00 mg/m2 n=9, >1.00 <1.50 mg/m2 n=6,
1.50 mg/m2 n=12
2.7.6.2.2-8 1 20S
20S %
(mg/m2) 1 4 8 11
1 24 1 1 24 1
80%
0.40 0.60 45 7 51 43 20 59 59 11 0 >0.60 1.00 50 21 63 66 41 66 66 8, 11 0
>1.00 <1.50 53 17 62 62 32 66 66 11 0 1.50 68 34 74 79 51 78 79 8 6
2.7.6.2.2-9 1 20S10%
(mg/m2)
0.40 0.60 >0.60 1.00 >1.00 <1.50 1.50
4 3 /4 (75%) 3 /9 (33%) 1 /6 (17%) 0 /11 (0%) 7 /30 (23%)
8 1 /3 (33%) 1 /9 (11%) 2 /6 (33%) 1 /11 (9%) 5 /29 (17%)
11 0 /4 (0%) 1 /9 (11%) 0 /5 (0%) 1 /10 (10%) 2 /28 (7%)
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2.7.6 98-104A 57
0.60 mg/m2
30 1
20S 2.7.6.2.2-3
20S r -0.066
1
2.7.6.2.2-3 20S N=30
(5)
1)
1 1 2 2 1 4 8 11 10 1
3 4
43 2.7.6.2.2-10 43
12.2 mg 0.7 40.8 mg 8
1 24 5
1 137 4
mL/m n
2
- 3 262 r - 6 6
3 6 8 1 11 12 13 1 1 16 1 18 1 2
1
2
3
6
8
1
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2.7.6 98-104A 58
2.7
.6.2
.2-1
0N
=43
(m
g/m
2 )0.
13(n
=3)
0.25
(n=4
)0.
40(n
=5)
0.60
(n=4
)0.
75(n
=3)
0.90
(n=6
)1.
08(n
=3)
1.30
(n=3
)1.
56(n
=12)
(n=4
3)1
(mg/
m2 )
N
3 4
5 4
3 6
3 3
12
43
SD0.
8 (0
.05)
1.
6 (0
.11)
2.
2 (0
.89)
3.
9 (0
.38)
5.
9 (0
.96)
6.
5 (0
.47)
7.
7 (0
.23)
8.
6 (1
.16)
10
.5 (2
.32)
6.
2 (3
.75)
0.
8 1.
6 2.
4 3.
8 6.
0 6.
4 7.
6 8.
4 10
.7
6.4
0.8,
0.8
1.5,
1.8
0.7,
3.1
3.5,
4.4
4.9,
6.8
6.0,
7.2
7.6,
8.0
7.6,
9.9
5.5,
13.2
0.
7,13
.2
(m
g)
N
3 4
5 4
3 6
3 3
12
43
SD1.
6 (0
.09)
3.
5 (1
.82)
3.
7 (1
.83)
7.
2(4.
70)
17.9
(8.1
2)
18.1
(11.
37)
14.8
(1.3
9)
19.5
(13.
14)
16.2
(8.7
5)
12.2
(9.5
6)
1.5
3.1
4.6
5.5
14.6
12
.8
15.2
17
.3
14.8
12
.0
1.5,
1.7
1.8,
6.1
0.7,
5.2
4.0,
14.1
12
.0,2
7.2
12.0
,40.
8 13
.3,1
6.0
7.6,
33.6
5.
5,.3
6.5
0.7,
40.8
N
3
4 5
4 3
6 3
3 12
43
SD
8 (0
) 9
(5.0
) 6
(3.2
) 8
(5.7
) 12
(4.0
) 11
(6.4
) 8
(0.6
) 9
(6.2
) 6
(2.9
) 8
(4.4
) 8
8 8
6 12
8
8 7
5 8
8,8
4,16
1,
8 4,
16
8,16
8,
24
7,8
4,16
2,
12
1,24
N
3
4 5
4 3
6 3
3 12
43
SD
32 (0
) 39
(26.
2)
24 (1
8.1)
31
(29.
7)
56 (2
4)
59 (4
4.3)
31
(1.7
) 40
(31.
7)
22 (1
7.8)
35
(26.
8)
32
36
32
20
53
33
32
36
19
32
32,3
2 11
,74
1,46
11
,74
33,8
1 32
,137
29
,32
11,7
4 4,
67
1,13
7
N
3
4 5
4 3
6 3
3 12
43
SD
2 (0
) 2
(1.3
) 2
(0.6
) 2
(1.4
) 3
(1.0
) 3
(1.6
) 2
(0)
2 (1
.5)
2 (0
.7)
2 (1
.1)
2 2
2 2
3 2
2 2
2 2
2,2
1,4
1,2
1,4
2,4
2,6
2,2
1,4
1,3
1,6
![Page 13: 6Î9Ô 98-104A 9Õ - pmda.go.jp · n O ^ 9 1 R I 1s2 Á9Ø2 1s4F5R(Â ] ... 0.75 3 17 9Ø18 19 0.90 6 20 9Ø21 22 23 24 25 1.08 3 26 9Ø27 28 1.30 3 29 9Ø30 31 1.56 12 32 9](https://reader031.vdocuments.us/reader031/viewer/2022022716/5c16e46109d3f263628cdb44/html5/thumbnails/13.jpg)
2.7.6 98-104A 59
56% 24/43 2 1 2 4 4
19% 8/43 2 0.25 0.60 1.30
1.56 mg/m2 1 0.75 0.90 mg/m2 2 2
2.7.6.2.2-11
2 8 7
4 21 0.90 mg/m2 1 3
4 4 2 4 2 8 6 PD
2
2.7.6.2.2-11 2
(mg/m2)0.25 6 16 4 PD 0.60 16 16 4 PD 0.75 17 16 4 PD
18 12 3 PD 0.90 20 24 6 PD
21 10 2.5 PD 1.30 31 16 4 a
1.56 35 12 3 b
ab
2)
30
2.7.6.2.2-12
5
2.7.6.2.2-12
![Page 14: 6Î9Ô 98-104A 9Õ - pmda.go.jp · n O ^ 9 1 R I 1s2 Á9Ø2 1s4F5R(Â ] ... 0.75 3 17 9Ø18 19 0.90 6 20 9Ø21 22 23 24 25 1.08 3 26 9Ø27 28 1.30 3 29 9Ø30 31 1.56 12 32 9](https://reader031.vdocuments.us/reader031/viewer/2022022716/5c16e46109d3f263628cdb44/html5/thumbnails/14.jpg)
2.7.6 98-104A 60
2.7.6.2.2-13 43 1
1 91%
39/43
2.7.6.2.2-13
(mg/m2)0.13(n=3)
0.25(n=4)
0.40(n=5)
0.60(n=4)
0.75(n=3)
0.90(n=6)
1.08(n=3)
1.30(n=3)
1.56(n=12) (n=43)
n (%) 3(100) 4(100) 5(100) 4(100) 3(100) 6(100) 3(100) 3(100) 12(100) 43(100)
n (%) 1(33) 4(100) 5(100) 4(100) 2(67) 5(83) 3(100) 3(100) 12(100) 39(91)
30 30
16 0.25 mg/m2 1 4
0.40 mg/m2 2 8 10 0.60 mg/m2 2 13 15 0.75
mg/m2 1 19 0.90 mg/m2 1 24 1.08 mg/m2 2
27 28 1.30 mg/m2 2 29 31 1.56 mg/m2 5
34 35 36 37 41
16 15 1 37 1.56 mg/m2
30
30 26%
11/43 0.25
mg/m2 50% 2/4 0.40 mg/m2 40% 2/5 1.08 mg/m2 67% 2/3 1.30 mg/m2
33% 1/3 1.56 mg/m2 33% 4/12
7% 3/43
2.7.6.2.2-14
![Page 15: 6Î9Ô 98-104A 9Õ - pmda.go.jp · n O ^ 9 1 R I 1s2 Á9Ø2 1s4F5R(Â ] ... 0.75 3 17 9Ø18 19 0.90 6 20 9Ø21 22 23 24 25 1.08 3 26 9Ø27 28 1.30 3 29 9Ø30 31 1.56 12 32 9](https://reader031.vdocuments.us/reader031/viewer/2022022716/5c16e46109d3f263628cdb44/html5/thumbnails/15.jpg)
2.7.6 98-104A 61
2.7.6.2.2-14N=43
(mg/m2) MedDRA PT (Cycle/Day)Grade
1.08 27 C2 / D11 2
C2 / D11 2
C2 / D11 3
1.30 31 C2 / D1 3
1.56 35 C3 / D17 2
Grade3 Grade4
Grade3 2.7.6.2.2-15
Grade3 2.7.6.2.2-16
Grade3 40% 17/43 Grade3
9% 4/43
7% 3/43 Grade3 2
Grade4 2.7.6.2.2-17 Grade4 7% 3/43
Grade4 4 0.25 mg/m2
16 0.60 mg/m2 31 1.30 mg/m2
Grade4
![Page 16: 6Î9Ô 98-104A 9Õ - pmda.go.jp · n O ^ 9 1 R I 1s2 Á9Ø2 1s4F5R(Â ] ... 0.75 3 17 9Ø18 19 0.90 6 20 9Ø21 22 23 24 25 1.08 3 26 9Ø27 28 1.30 3 29 9Ø30 31 1.56 12 32 9](https://reader031.vdocuments.us/reader031/viewer/2022022716/5c16e46109d3f263628cdb44/html5/thumbnails/16.jpg)
2.7.6 98-104A 62
2.7
.6.2
.2-1
5G
rade
3N
=43
(m
g/m
2 )M
edD
RA
/J v
8.0
(SO
C)
(PT
) 0.
13(n
=3)
0.25
(n=4
)0.
40(n
=5)
0.60
(n=4
)0.
75(n
=3)
0.90
(n=6
)1.
08(n
=3)
1.30
(n=3
)1.
56(n
=12)
Gra
de3
%
2 (5
0%)
2 (4
0%)
1 (2
5%)
2
(33%
) 1
(33%
) 2
(67%
) 7
(58%
)
1
(25%
)
1 (1
7%)
1 (3
3%)
1 (3
3%)
4 (3
3%)
1
(25%
)
1 (3
3%)
1 (8
%)
2 (1
7%)
1
(17%
)
1
(8%
)
1
(33%
)
1 (2
5%)
1
(25%
)
4
(33%
)
1 (2
5%)
3 (2
5%)
2 (1
7%)
1 (8
%)
1
(25%
)
1
(25%
)
1
(25%
) 1
(20%
)
1
(33%
) 1
(8%
)
1 (2
5%)
1
(33%
) 1
(8%
)
1
(20%
)
1 (1
7%)
1
(33%
) 2
(17%
)
1 (1
7%)
1
(33%
) 2
(17%
)
1 (3
3%)
1
(20%
)
1
(17%
)
1
(8%
)
1 (1
7%)
1 (8
%)
1 (2
0%)
1
(33%
)
1
(33%
)
1 (2
0%)
1 (2
0%)
1 (8
%)
1 (8
%)
![Page 17: 6Î9Ô 98-104A 9Õ - pmda.go.jp · n O ^ 9 1 R I 1s2 Á9Ø2 1s4F5R(Â ] ... 0.75 3 17 9Ø18 19 0.90 6 20 9Ø21 22 23 24 25 1.08 3 26 9Ø27 28 1.30 3 29 9Ø30 31 1.56 12 32 9](https://reader031.vdocuments.us/reader031/viewer/2022022716/5c16e46109d3f263628cdb44/html5/thumbnails/17.jpg)
2.7.6 98-104A 63
2.7
.6.2
.2-1
6G
rade
3N
=43
(m
g/m
2 )M
edD
RA
/J v
8.0
(SO
C)
(PT
) 0.
13(n
=3)
0.25
(n=4
)0.
40(n
=5)
0.60
(n=4
)0.
75(n
=3)
0.90
(n=6
)1.
08(n
=3)
1.30
(n=3
)1.
56(n
=12)
Gra
de3
(%
)
1 (2
5%)
1
(17%
) 1
( 33%
) 2
( 67%
) 6
(50%
)
1
(25%
)
1 (1
7%)
1 (3
3%)
1 (3
3%)
4 (3
3%)
1
(25%
)
1 (3
3%)
1 (8
%)
2 (1
7%)
1
(17%
)
1
(8%
)
1
(33%
)
3
(25%
)
3
(25%
)
1 (3
3%)
2 (1
7%)
1
(33%
) 2
(17%
)
1 (3
3%)
1 (3
3%)
1 (3
3%)
1 (1
7%)
1 (1
7%)
2.7
.6.2
.2-1
7G
rade
4N
=43
(m
g/m
2 )M
edD
RA
/J v
8.0
(SO
C)
(PT
) 0.
13(n
=3)
0.25
(n=4
)0.
40(n
=5)
0.60
(n=4
)0.
75(n
=3)
0.90
(n=6
)1.
08(n
=3)
1.30
(n=3
)1.
56(n
=12)
Gra
de4
(%
)
1 (2
5%)
1
(25%
)
1 (3
3%)
1
(25%
)
1
(25%
)
1
(33%
)
![Page 18: 6Î9Ô 98-104A 9Õ - pmda.go.jp · n O ^ 9 1 R I 1s2 Á9Ø2 1s4F5R(Â ] ... 0.75 3 17 9Ø18 19 0.90 6 20 9Ø21 22 23 24 25 1.08 3 26 9Ø27 28 1.30 3 29 9Ø30 31 1.56 12 32 9](https://reader031.vdocuments.us/reader031/viewer/2022022716/5c16e46109d3f263628cdb44/html5/thumbnails/18.jpg)
2.7.6 98-104A 64
2.7.6.2.2-18
16% 7/43 0.60 mg/m2 25% 1/4 1.30 mg/m2 33%
1/3 1.56 mg/m2 42% 5/12
Grade3 4 31 33 35
41 4 1 Grade3
4 2 31 35
2.7.6.2.2-18
(mg/m2) MedDRA PT (Cycle / Day)Grade
0.60 13 a C1 / D11 2 1.30 31 C2 / D1 3 1.56 32 c C1 / D4 2
33 b C1 / D16 3 35 b C3 / D4 3
b C3 / D17 3 40 d C1 / D4 2
C1 / D8 2 C1 / D8 2
41 b C1 / D1 3 b C2 / D14 2
b C2 / D16 3 ab MPI Product safety MedWatch CIOMSc ECG
d PD
DLT
DLT 2.7.6.2.2-19 1.30 mg/m2 DLT
1.56 mg/m2 25% 3/12 1 DLT
3 Grade3 1 Grade3
![Page 19: 6Î9Ô 98-104A 9Õ - pmda.go.jp · n O ^ 9 1 R I 1s2 Á9Ø2 1s4F5R(Â ] ... 0.75 3 17 9Ø18 19 0.90 6 20 9Ø21 22 23 24 25 1.08 3 26 9Ø27 28 1.30 3 29 9Ø30 31 1.56 12 32 9](https://reader031.vdocuments.us/reader031/viewer/2022022716/5c16e46109d3f263628cdb44/html5/thumbnails/19.jpg)
2.7.6 98-104A 65
2.7.6.2.2-19 DLT
(mg/m2)<0.4(n=7)n (%)
0.40 - 0.60(n=9)n (%)
>0.60 - 1.00(n=9)n (%)
>1.00 - <1.50 (n=6)n (%)
1.50(n=12)n (%)
(n=43)n(%)
DLT 0 0 0 0 3 (25) 3 (7)
DLT MedDRA PT 0 0 0 0 0 0 0 0 0 0 3 3 0 0 0 0 1 1
2.7.6.2.2-20
2.7.6.2.2-21
43 1
79% 34/43 65% 28/43 44% 19/43
44% 19/43 35% 15/43 35% 15/43
91% 39/43
74% 32/43 37% 16/43
35% 15/43 26% 11/43 23% 10/43
![Page 20: 6Î9Ô 98-104A 9Õ - pmda.go.jp · n O ^ 9 1 R I 1s2 Á9Ø2 1s4F5R(Â ] ... 0.75 3 17 9Ø18 19 0.90 6 20 9Ø21 22 23 24 25 1.08 3 26 9Ø27 28 1.30 3 29 9Ø30 31 1.56 12 32 9](https://reader031.vdocuments.us/reader031/viewer/2022022716/5c16e46109d3f263628cdb44/html5/thumbnails/20.jpg)
2.7.6 98-104A 66
2.7
.6.2
.2-2
0N
=43
(m
g/m
2 )M
edD
RA
/J v
8.0
(SO
C)
(PT
) 0.
13(n
=3)
0.25
(n=4
)0.
40(n
=5)
0.60
(n=4
)0.
75(n
=3)
0.90
(n=6
)1.
08(n
=3)
1.30
(n=3
)1.
56(n
=12)
(%
) 3
(100
%)
4 (1
00%
) 5
(100
%)
4 (1
00%
) 3
(100
%)
6 (1
00%
) 3
(100
%)
3 (1
00%
) 12
(100
%)
2 (6
7%)
4 (1
00%
) 5
(100
%)
3 (7
5%)
1 (3
3%)
6 (1
00%
) 3
(100
%)
3 (1
00%
) 11
(92%
) 1
(33%
) 4
(100
%)
5 (1
00%
) 2
(50%
) 1
(33%
) 4
(67%
) 3
(100
%)
3 (1
00%
) 11
(92%
)
2 (5
0%)
3
(50%
) 1
(33%
) 2
(67%
) 7
(58%
) 1
(33%
)
2 (4
0%)
1 (1
7%)
1 (3
3%)
2
(17%
)
1
(20%
)
1
(17%
) 1
(33%
) 1
(33%
) 1
(8%
)
1 (1
7%)
1 (3
3%)
2
(17%
)
2
(40%
)
2
(33%
)
1
(17%
)
1
(17%
)
3 (1
00%
) 4
(100
%)
4 (8
0%)
3 (7
5%)
1 (3
3%)
5 (8
3%)
3 (1
00%
) 2
(67%
) 11
(92%
) 2
(67%
) 3
(75%
) 3
(60%
) 3
(75%
) 1
(33%
) 4
(67%
)
2 (6
7%)
10 (8
3%)
1 (2
0%)
2 (5
0%)
1 (3
3%)
1 (1
7%)
2 (6
7%)
4
(33%
)
1
(20%
)
1
(17%
) 1
(33%
) 1
(33%
) 1
(8%
)
1 (1
7%)
1 (3
3%)
2
(17%
)
2 (5
0%)
1 (3
3%)
1
(8%
)
1
(20%
)
1
(17%
)
1
(8%
)
1
(8%
) 1
(33%
)
1
(20%
)
3
(100
%)
1 (2
5%)
3 (6
0%)
3 (7
5%)
2 (6
7%)
5 (8
3%)
3 (1
00%
) 2
(67%
) 11
(92%
)
1
(20%
) 1
(25%
) 2
(67%
) 1
(17%
) 1
(33%
) 2
(67%
) 11
(92%
) 2
(67%
) 1
(25%
) 2
(40%
) 2
(50%
) 1
(33%
) 2
(33%
) 2
(67%
) 1
(33%
) 6
(50%
)
1
(20%
) 2
(50%
) 1
(33%
) 1
(17%
) 2
(67%
) 1
(33%
) 7
(58%
)
1 (2
5%)
1 (3
3%)
1 (1
7%)
2 (6
7%)
1 (3
3%)
7 (5
8%)
1 (3
3%)
1 (2
5%)
1 (3
3%)
1 (1
7%)
1 (3
3%)
4
(33%
) 1
(33%
)
1 (3
3%)
1 (3
3%)
1 (2
5%)
1
(8%
)
1
(8%
)
![Page 21: 6Î9Ô 98-104A 9Õ - pmda.go.jp · n O ^ 9 1 R I 1s2 Á9Ø2 1s4F5R(Â ] ... 0.75 3 17 9Ø18 19 0.90 6 20 9Ø21 22 23 24 25 1.08 3 26 9Ø27 28 1.30 3 29 9Ø30 31 1.56 12 32 9](https://reader031.vdocuments.us/reader031/viewer/2022022716/5c16e46109d3f263628cdb44/html5/thumbnails/21.jpg)
2.7.6 98-104A 67 (
mg/
m2 )
Med
DR
A/J
v8.
0 (
SOC
) (
PT)
0.13
(n=3
)0.
25(n
=4)
0.40
(n=5
)0.
60(n
=4)
0.75
(n=3
)0.
90(n
=6)
1.08
(n=3
)1.
30(n
=3)
1.56
(n=1
2)
1
(33%
)
1
(8%
)
1
(33%
)
1
(20%
)
1 (2
5%)
1 (2
5%)
1
(33%
) 1
(25%
) 1
(20%
) 1
(25%
)
3 (5
0%)
1 (3
3%)
2 (6
7%)
8 (6
7%)
1 (3
3%)
1 (2
5%)
1
(17%
)
6
(50%
)
1 (2
5%)
1
(17%
) 1
(33%
) 1
(33%
) 4
(33%
)
1
(20%
)
1
(17%
)
1 (3
3%)
2 (1
7%)
1
(33%
) 1
(8%
)
1
(8%
)
1
(8%
)
2 (5
0%)
2 (4
0%)
1 (2
5%)
2
(33%
) 1
(33%
) 2
(67%
) 5
(42%
)
1 (2
5%)
1
(25%
)
2 (3
3%)
1 (3
3%)
2 (6
7%)
4 (3
3%)
1
(25%
) 1
(20%
)
1
(33%
) 1
(8%
)
1 (3
3%)
1 (2
5%)
1
(20%
)
1
(20%
) 1
(25%
)
1 (1
7%)
1 (3
3%)
2 (6
7%)
7 (5
8%)
1 (2
0%)
1 (1
7%)
1 (3
3%)
2 (6
7%)
6 (5
0%)
3 (2
5%)
1
(25%
)
1
(25%
) 1
(20%
)
1 (3
3%)
4 (6
7%)
2 (6
7%)
1 (3
3%)
3 (2
5%)
1
(17%
) 1
(33%
)
2 (1
7%)
1 (3
3%)
1 (1
7%)
1 (8
%)
1
(25%
)
1 (1
7%)
1 (3
3%)
1 (2
0%)
1 (1
7%)
1 (1
7%)
1 (3
3%)
1 (1
7%)
1 (2
5%)
1 (2
0%)
1 (2
5%)
2
(33%
)
1 (3
3%)
3 (2
5%)
1
(25%
)
1 (1
7%)
1
(33%
) 2
(17%
)
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2.7.6 98-104A 68 (
mg/
m2 )
Med
DR
A/J
v8.
0 (
SOC
) (
PT)
0.13
(n=3
)0.
25(n
=4)
0.40
(n=5
)0.
60(n
=4)
0.75
(n=3
)0.
90(n
=6)
1.08
(n=3
)1.
30(n
=3)
1.56
(n=1
2)
1 (2
5%)
1
(17%
)
1
(8%
)
1
(20%
)
1
(17%
)
1
(25%
) 1
(20%
)
2
(33%
) 1
(33%
) 1
(33%
) 2
(17%
)
1
(33%
) 1
(33%
) 1
(8%
)
2 (3
3%)
1 (2
5%)
1 (2
0%)
1 (8
%)
1 (3
3%)
1 (2
5%)
2
(33%
)
1 (3
3%)
2 (1
7%)
1 (3
3%)
2 (3
3%)
1
(33%
) 1
(8%
)
1 (2
5%)
1 (8
%)
1 (3
3%)
2 (5
0%)
1 (3
3%)
3
(25%
) 1
(33%
) 1
(25%
)
2 (1
7%)
1 (3
3%)
1
(8%
)
1 (2
5%)
1
(33%
)
1 (2
0%)
1
(33%
) 1
(17%
)
1 (3
3%)
1
(20%
)
1
(17%
)
1 (3
3%)
1
(33%
)
1 (3
3%)
1 (3
3%)
1 (3
3%)
1 (2
5%)
1
(17%
)
1 (3
3%)
1
(33%
) 1
(25%
)
1
(17%
)
1
(33%
)
2
(33%
)
1
(8%
)
1 (1
7%)
1 (8
%)
1
(17%
)
2 (4
0%)
1 (1
7%)
2
(40%
)
1 (1
7%)
1
(20%
)
1
(33%
)
1 (8
%)
1 (3
3%)
1
(8%
)
1
(33%
) 1
(33%
)
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2.7.6 98-104A 69 (
mg/
m2 )
Med
DR
A/J
v8.
0 (
SOC
) (
PT)
0.13
(n=3
)0.
25(n
=4)
0.40
(n=5
)0.
60(n
=4)
0.75
(n=3
)0.
90(n
=6)
1.08
(n=3
)1.
30(n
=3)
1.56
(n=1
2)
1
(33%
) 1
(33%
)
1
(25%
)
1
(25%
)
1 (8
%)
1 (8
%)
2.7
.6.2
.2-2
1N
=43
(m
g/m
2 )M
edD
RA
/J v
8.0
(SO
C)
(PT
) 0.
13(n
=3)
0.25
(n=4
)0.
40(n
=5)
0.60
(n=4
)0.
75(n
=3)
0.90
(n=6
)1.
08(n
=3)
1.30
(n=3
)1.
56(n
=12)
(%
) 1
(33%
) 4
(100
%)
5 (1
00%
) 4
(100
%)
2 (6
7%)
5 (8
3%)
3 (1
00%
) 3
(100
%)
12 (1
00%
)
1 (3
3%)
4 (1
00%
) 5
(100
%)
3 (7
5%)
1 (3
3%)
5 (8
3%)
3 (1
00%
) 3
(100
%)
10 (8
3%)
4
(100
%)
5 (1
00%
) 2
(50%
) 1
(33%
) 4
(67%
) 3
(100
%)
3 (1
00%
) 10
(83%
)
2 (5
0%)
3
(50%
) 1
(33%
) 2
(67%
) 7
(58%
) 1
(33%
)
2 (4
0%)
1 (1
7%)
1 (3
3%)
2
(17%
)
1 (1
7%)
1 (3
3%)
2
(17%
)
1 (2
5%)
1 (2
0%)
3 (7
5%)
3
(50%
) 2
(67%
) 1
(33%
) 9
(75%
)
1 (2
5%)
2
(50%
)
3 (5
0%)
1
(33%
) 9
(75%
)
1
(20%
) 2
(50%
)
1 (1
7%)
2 (6
7%)
3
(25%
)
1 (1
7%)
1 (3
3%)
2
(17%
)
1
(20%
)
1 (8
%)
1 (3
3%)
2 (3
3%)
1
(33%
) 10
(83%
)
1 (1
7%)
10 (8
3%)
1 (3
3%)
1 (1
7%)
1
(33%
) 7
(58%
)
1 (1
7%)
7 (5
8%)
4 (3
3%)
3 (2
5%)
1 (8
%)
1
(17%
) 1
(33%
) 1
(33%
) 7
(58%
)
6
(50%
)
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2.7.6 98-104A 70 (
mg/
m2 )
Med
DR
A/J
v8.
0 (
SOC
) (
PT)
0.13
(n=3
)0.
25(n
=4)
0.40
(n=5
)0.
60(n
=4)
0.75
(n=3
)0.
90(n
=6)
1.08
(n=3
)1.
30(n
=3)
1.56
(n=1
2)
1
(33%
) 1
(33%
) 3
(25%
)
1 (3
3%)
1 (8
%)
1 (8
%)
1
(17%
)
1
(33%
) 5
(42%
)
1 (3
3%)
4 (3
3%)
1 (8
%)
2
(33%
) 1
(33%
) 1
(33%
) 2
(17%
)
1 (1
7%)
1 (3
3%)
1
(8%
)
1 (1
7%)
1 (8
%)
1
(33%
)
1
(25%
)
1 (1
7%)
1
(33%
) 1
(8%
)
1 (1
7%)
1
(33%
) 1
(8%
)
1 (2
5%)
2
(17%
)
2
(17%
)
1
(33%
)
1
(33%
)
1
(8%
)
1
(8%
)
1
(8%
)
1
(8%
)
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2.7.6 98-104A 71
0.25 mg/m2 7 0.40 0.60 mg/m2
9 >0.60 1.00 mg/m2 9 >1.00 <1.50 mg/m2 6 1.50 mg/m2
12
2.7.6.2.2-22
2.7.6.2.2-22 10% N=43
(mg/m2) n (%)
MedDRA/Jv8.0 (PT)
0.25 (n=7)
0.400.60 (n=9)
>0.601.00 (n=9)
>1.00<1.50 (n=6)
1.50 (n=12)
(n=43)
7 (100%) 9 (100%) 9 (100%) 6 (100%) 12 (100%) 43 (100%)
5 (71%) 7 (78%) 5 (56%) 6 (100%) 11 (92%) 34 (79%)5 (71%) 6 (67%) 5 (56%) 2 (33%) 10 (83%) 28 (65%)
2 (22%) 3 (33%) 3 (50%) 11 (92%) 19 (44%)3 (43%) 4 (44%) 3 (33%) 3 (50%) 6 (50%) 19 (44%)
2 (22%) 3 (33%) 3 (50%) 7 (58%) 15 (35%) 3 (33%) 2 (22%) 3 (50%) 7 (58%) 15 (35%) 1 (11%) 2 (22%) 3 (50%) 7 (58%) 13 (30%)
1 (14%) 1 (11%) 2 (22%) 3 (50%) 4 (33%) 11 (26%) 1 (11%) 1 (11%) 3 (50%) 6 (50%) 11 (26%) 3 (33%) 2 (22%) 2 (33%) 4 (33%) 11 (26%)
2 (29%) 1 (11%) 6 (50%) 9 (21%) 1 (14%) 1 (11%) 2 (22%) 1 (17%) 4 (33%) 9 (21%)
1 (11%) 1 (11%) 2 (33%) 4 (33%) 8 (19%) 1 (14%) 2 (22%) 1 (11%) 1 (17%) 2 (17%) 7 (16%) 1 (14%) 2 (22%) 1 (17%) 1 (8%) 5 (12%)
1 (11%) 1 (11%) 2 (33%) 1 (8%) 5 (12%) 1 (11%) 1 (11%) 1 (17%) 2 (17%) 5 (12%) 1 (11%) 1 (11%) 2 (33%) 1 (8%) 5 (12%) 1 (11%) 1 (11%) 1 (17%) 2 (17%) 5 (12%)
79% 34/43 32
65% 22/34
Grade1 2 Grade3 7% 3/43 0.25 mg/m2 1.30 mg/m2
1.56 mg/m2 1 Grade4
44% 19/43 0.25 mg/m2 0% 0/7 0.40 0.60
mg/m2 22% 2/9 >0.60 1.00 mg/m2 33% 3/9 >1.00 <1.50 mg/m2 50% 3/6
1.50 mg/m2 92% 11/12
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2.7.6 98-104A 72
Grade2 >1.00 <1.50 mg/m2 1.50 mg/m2 1
17 Grade1 26% 11/43
1 1.50 mg/m2 10 >0.60 1.00 mg/m2 1
35% 15/43 0.25 mg/m2 0% 0/7 0.40 0.60
mg/m2 33% 3/9 >0.60 1.00 mg/m2 22% 2/9 >1.00 <1.50 mg/m2 50% 3/6
1.50 mg/m2 58% 7/12
35% 15/43 15
2
>1.00 <1.50 mg/m2 1.50 mg/m2 50% 58%
Grade1 2 Grade3
1.50 mg/m2 5% 2/43
30% 13/43 0.25 mg/m2 0% 0/7 0.40 0.60
mg/m2 11% 1/9 >0.60 1.00 mg/m2 22% 2/9 >1.00 <1.50 mg/m2 50% 3/6
1.50 mg/m2 58% 7/12
Grade3 9% 4/43 0.40 0.60 mg/m2 1 1.50 mg/m2
3 1.50 mg/m2 Grade3 1
DLT
19% 8/43 0.25 mg/m2 0%
0/7 0.40 0.60 mg/m2 11% 1/9 >0.60 1.00 mg/m2 11% 1/9 >1.00 <1.50
mg/m2 33% 2/6 1.50 mg/m2 33% 4/12
1.00 mg/m2 1.00 mg/m2 8% 2/25
1.00 mg/m2 33% 6/18
2.7.6.2.2-23
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2.7.6 98-104A 73
2.7.6.2.2-23
mg/m2
0.25(n=7)n (%)
0.40 - 0.60(n=9)n (%)
>0.60 - 1.00(n=9)n (%)
>1.00 - <1.50(n=6)n (%)
1.50(n=12)n (%)
(n=43)n(%)
N 0 4 2 2 11 19
1 (25) 0 0 0 1(5) 3 (75) 1 (50) 2 (100) 7 (64) 13 (68)
0 1 (50) 0 4 (36) 5 (26)
N 7 5 7 4 1 24 0 1 (20) 0 2 (50) 0 3 (13)
7 (100) 4 (80) 7 (100) 2 (50) 1 (100) 21 (88)
44% 19/43 Grade1 17
Grade2 2 74% 14/19 26% 5/19
13% 3/24
8 6
8 5
Grade3 4 3
20S
20S 2.7.6.2.2-24
43 31 20S 31
20S 70% 10 70% 80% 15
80% 6
DLT Grade3
80% 80%
90%
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2.7.6 98-104A 74
2.7.6.2.2-24 20S
20S (%) <70
(n=10)70 <80
(n=15)80
(n=6) (n=31)DLT
N (%) 0 0 3 (50) 3 (10) 90% a 0, 26 0, 18 15, 85 3, 23
Grade3N (%) 0 5 (33) 5 (83) 10 (32) 90% a 0, 26 14, 58 42, 99 19, 49
N (%) 0 4 (27) 3 (50) 7 (23) 90% a 0, 26 10, 51 15, 85 11, 38
N (%) 1 (10) 3 (20) 3 (50) 7 (23) 90% a 1, 39 6, 44 15, 85 11, 38
a
(i)
1 2.7.6.2.2-4
0.40 0.60 0.75 0.90 1.08 1.30 1.56 mg/m2 329 316 251 191
593 485 293 109 /L 160
400 109 /L 1.56 mg/m2 11
0.90 1.56 mg/m2
11 2 1
0.90 mg/m2
35% 15/43
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2.7.6 98-104A 75
2.7.6.2.2-4 1 0.40 mg/m2
1 2.7.6.2.2-5
0.40 0.60 0.75 0.90 1.08 1.30 1.56 mg/m2 106 104 131 114
105 124 119 g/L 0.75 mg/m2 130
170 g/L 2 1
79% 34/43
74% 32/43 65% 22/34
109 /L
0.40 mg/m2
0.60 mg/m2
0.75 mg/m2
0.90 mg/m2
1.08 mg/m2
1.30 mg/m2
1.56 mg/m2
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2.7.6 98-104A 76
2.7.6.2.2-5 1 0.40 mg/m2
1 2.7.6.2.2-6
0.40 0.60 0.75 0.90 1.08 1.30 1.56 mg/m2 4.5 4.9 5.2 4.2 4.0
5.2 5.7 109 /L 1.5 8.8 109 /L
1.08 mg/m2 1 28
2 1 2.5
27.7 109 /L 1 4 8 15 2 1
30.8 24.5 26.6 25.5 109 /L
Grade3 0.90 1.08 1.56 mg/m2
1 3
g/L
0.40 mg/m2
0.60 mg/m2
0.75 mg/m2
0.90 mg/m2
1.08 mg/m2
1.30 mg/m2
1.56 mg/m2
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2.7.6 98-104A 77
2.7.6.2.2-6 1 0.40 mg/m2
109 /L
0.40 mg/m2
0.60 mg/m2
0.75 mg/m2
0.90 mg/m2
1.08 mg/m2
1.30 mg/m2
1.56 mg/m2
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2.7.6 98-104A 78
(ii)
1 2.7.6.2.2-7
0.40 0.60 0.75 0.90 1.08 1.30 1.56 mg/m2 139 139 139 138
133 140 138 mmol/L 1.08 mg/m2 136
144 109 /L 1.08 mg/m2
1.08 mg/m2 2 1
1.08 mg/m2 26 Grade1
1 4 Grade3 1.08 mg/m2
27 Grade1 2
Grade3
2.7.6.2.2-7 1 0.40 mg/m2
mm
ol/L
0.40 mg/m2
0.60 mg/m2
0.75 mg/m2
0.90 mg/m2
1.08 mg/m2
1.30 mg/m2
1.56 mg/m2
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2.7.6 98-104A 79
1 2.7.6.2.2-8
0.40 0.60 0.75 0.90 1.08 1.30 1.56 mg/m2 4.4 4.0 4.5 4.1 4.8
4.1 4.0 mmol/L 3.5 5.1 mmol/L
0.40 mg/m2
Grade3 0.25 mg/m2 1 Grade3
2.7.6.2.2-8 1 0.40 mg/m2
mm
ol/L
0.40 mg/m2
0.60 mg/m2
0.75 mg/m2
0.90 mg/m2
1.08 mg/m2
1.30 mg/m2
1.56 mg/m2
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2.7.6 98-104A 80
2.7.6.2.2.3
2 2 1 4 8 11 10
MTD 1.30 mg/m2
DLT 1.56 mg/m2 3 DLT Grade3 3 Grade3
1
79% 34/43
Grade1 2
1 20S
20S 72 96
2 1.56 mg/m2 NSCLC
PR 1.30 mg/m2 SD
1.3
mg/m2
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2.7.6 LCCC9834/MSKCC00-31 81
2.7.6.2.3 LCCC9834/MSKCC00-31 5.3.5.3.1
2.7.6.2.3.1
2.7.6.2.3- 1
2.7.6.2.3- 1
LCCC9834/MSKCC00-31Stinchcombe T, Mitchell BS, Adams J, Elliott P, Shea TC, Orlowski RZ. PS-341 is active in multiple myeloma: a preliminary report of a phase I trial of the proteasome inhibitor PS-341 in patients with hematologic malignancies. Abstract No. 2219. Blood2000;96:516a.
Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol. 2002 Nov 15;20(22):4420-7.
2 4MTD DLT
2 4PBMCs 20S
PBMCs
PBMCs 20S
PBMCs 20S
IL-6 20SPBMCs
1)AMLCML
ALLCLL
HDNHL
MMMDS
RAEB RAEB-T RAEB
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2.7.6 LCCC9834/MSKCC00-31 82
2)
3)4)
444
25)66)187) ECOG 0 1 28)
2,000 /mm3
1,000 /mm3
50,000 /mm3
8.0 mg/dL 9) 38.5
10) 2.5 mg/dL
> 50 mL/min 11)
AST < N 2.5 NALT < N 2.5
< N 1.5 12)
ECGECG
613)
1)2)3) New York Heart Association NYHA Class
4)5) NCI-CTC Grade1
6)
DLT MTD 3 6MTD 12
27
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2.7.6 LCCC9834/MSKCC00-31 83
DLT 1 Grade4 Grade4Grade3 Grade3
MTD DLT 33% 2.5 mg 25 mg
1 0.40 1.04 1.20 1.38 1.59 1.83 mg/m2
0.40 1.38 mg/m2
1 1 2 4 1 4 8 11 15 18 22 2514 17 6
3 3 1 DLT3 1 DLT
3 3 DLTDLT >33% MTD
1 1233% DLT MTD
14
20S
PBMCs IL-6
ITT Intent-To-Treat
ECOGX
MTD DLT90%
SAS ver. 8.02
21999 11 82001 7 26
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2.7.6 LCCC9834/MSKCC00-31 84
2.7.6.2.3.2
(1)
University of North Carolina UNC 20 Memorial Sloan-Kettering Cancer
Center MSKCC 7 27 0.40 mg/m2 3 1.04 mg/m2
12 1.20 mg/m2 7 1.38 mg/m2 5
1 15 2.7.6.2.3-2
2.7.6.2.3-2
(mg/m2)N
0.40 3 1 2 31.04 12 4 5 6
205 16 17 18 19 20 21 206 2071.20 7 7 8 9
12 13 204 141.38 5 10 201 202
203 11 DLT
0.40 mg/m2 1.04 mg/m2 1.20 mg/m2 3
DLT 1.38 mg/m2 3 1 DLT
10 Grade3 3
6 5 1 DLT 202 Grade3
1.38 mg/m2 1.20 mg/m2 12
1.20 mg/m2 4 2 DLT 12 Grade3
13 Grade3 DLT 2
1.20 mg/m2 MTD
1.04 mg/m2 12
2001 7 1.04 mg/m2 9 UNC MSKCC
9 3 DLT Grade3 2 Grade3
1 MTD 1.04 mg/m2
2.7.6.2.3-1 1
27 ITT
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2.7.6 LCCC9834/MSKCC00-31 85
27
ITT27
2.7.6.2.3-1
(2)
2.7.6.2.3-3 70% 19/27
0.40 mg/m2 100% 3/3 1.04 mg/m2 75% 9/12 1.20 mg/m2
71% 5/7 1.38 mg/m2 40% 2/5
37% 10/27 0.40 mg/m2 33%
1/3 1.04 mg/m2 8% 1/12 1.20 mg/m2 57% 4/7 1.38 mg/m2 80%
4/5
2.7.6.2.3-3
(mg/m2)0.40(n=3)n (%)
1.04(n=12)n (%)
1.20(n=7)n (%)
1.38(n=5)n (%)
(n=27)n (%)
3 (100) 12 (100) 7 (100) 5 (100) 27 (100) 1 2 (67) 8 (67) 2 (29) 2 (40) 14 (52)
a 3 (100) 9 (75) 5 (71) 2 (40) 19 (70) 1 (33) 1 (8) 4 (57) 4 (80) 10 (37)
b 0 0 1 (14) 2 (40) 3 (11) 0 2 (17) 0 0 2 (7) 0 1 (8) 0 0 1 (4)
a 100%b 2 1 1
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2.7.6 LCCC9834/MSKCC00-31 86
(3)
27 2.7.6.2.3-4 1.20 mg/ 1
ECOG ECOG
63% 17/27 74% 20/27
56 22 77
75 kg 170 cm ECOG 1 58%
15/26 2 19% 5/26 74% 20/26 0 23% 6/26
2.7.6.2.3-4 N=27
mg/m2
0.40(n=3)
1.04(n=12)
1.20(n=7)
1.38(n=5) (n=27)
n (%) 3 (100) 5 (42) 6 (86) 3 (60) 17 (63)
0 7 (58) 1 (14) 2 (40) 10 (37) n (%)
2 (67) 8 (67) 5 (71) 5 (100) 20 (74) 1 (33) 4 (33) 2 (29) 0 7 (26)
N 3 12 7 5 27
SD 37 (13.0) 53 (12.5) 65 (7.9) 61 (12.3) 56 (13.7) 44.0 53.0 63.0 65.0 55.0
22, 45 31, 76 53, 77 43, 74 22, 77 kg
N 3 12 7 5 27 SD 81 (26.4) 72 (13.5) 81 (17.3) 69 (17.3) 75 (16.5)
82.0 74.0 81.6 76.7 75.8 53, 106 54, 94 59, 112 50, 90 50, 112
cm N 3 12 7 5 27
SD 177 (12.2) 168 (14.7) 171 (9.3) 172 (10.7) 170 (12.2) 174.0 163.0 169.0 172.5 169.0
166, 190 151, 196 159, 188 160, 186 151, 196 ECOG n (%)
0 2 (67) 1 (8) 2 (33) 1 (20) 6 (23) 1 0 10 (83) 2 (33) 3 (60) 15 (58) 2 1 (33) 1 (8) 2 (33) 1 (20) 5 (19)
0 0 1 0 1
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2.7.6 LCCC9834/MSKCC00-31 87
27 2.7.6.2.3-5
44% 12/27
33% 9/27 15% 4/27 4% 1/27 POEMS
MDS 4% 1/27 12
1 6 3
5 204 205 A 3 17 19 20 B 1
16 4 4 13 14 21
27 93% 25/27
41% 11/27 37% 10/27
4 3
12
2.7.6.2.3-5
mg/m2
0.40(n=3)
1.04(n=12)
1.20(n=7)
1.38(n=5) (n=27)
n (%) /
a 0 9 (75) 3 (43) 0 12 (44)
2 (67) 1 (8) 0 1 (20) 4 (15) 1 (33) 2 (17) 3 (43) 3 (60) 9 (33)
0 0 0 1 (20) 1 (4) b 0 0 1 (14) 0 1 (4)
N 3 12 7 5 27 SD 5 (2.3) 4 (3.1) 3 (2.3) 4 (2.5) 4 (2.7)
4 3 2 2 3 4, 8 1, 12 1, 7 2, 7 1, 12
n (%) 3 (100) 11 (92) 6 (86) 5 (100) 25 (93) 2 (67) 5 (42) 2 (29) 2 (40) 11 (41)
/ 3 (100) 4 (33) 1 (14) 2 (40) 10 (37) 1 (33) 3 (25) 1 (14) 2 (40) 7 (26)
0 3 (25) 2 (29) 0 5 (19) 0 3 (25) 2 (29) 1 (20) 6 (22) 0 2 (17) 2 (29) 1 (20) 5 (19)
1 (33) 0 0 2 (40) 3 (11) 0 3 (25) 0 0 3 (11) 0 0 1 (14) 0 1 (4)
a 14b 9 POEMS
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2.7.6 LCCC9834/MSKCC00-31 88
(4)
1)
ITT
2.7.6.2.3-6
14
2.7.6.2.3-6
CR
PR 50%
SD 50% 25%
PD 25%
PR 4 2
25
ITT 27 2.7.6.2.3-7 PR 30%
8/27 1.04 mg/m2 4 1.20 mg/m2 1.38 mg/m2 2
0.40 mg/m2 8 5
4 1.04mg/m2 1 1.20mg/m2 3
1 1.20mg/m2 2 1.38 mg/m2
2.7.6.2.3-7 ITT N=27
mg/m2
0.40(n=3)n (%)
1.04(n=12)n (%)
1.20(n=7)n (%)
1.38(n=5)n (%)
(n=27)n (%)
CR+PR 0 4 (33) 2 (29) 2 (40) 8 (30) SD 0 1 (8) 0 0 1 (4) PD 3 (100) 6 (50) 4 (57) 2 (40) 15 (56)
0 1 (8) 1 (14) 1 (20) 3 (11)
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2.7.6 LCCC9834/MSKCC00-31 89
13 1.04 mg/m2
9 1.20 mg/m2 4 13
2.7.6.2.3-8 46% 6/13 SD 8% 1/13 PD 31%
4/13 15% 2/13 2 9 19
9 1.20 mg/m2 POEMS
19 1.04 mg/m2 CT
6 1.04 mg/m2 4 1.20 mg/m2 2 1.04 mg/m2
1 4 CR
2.7.6.2.3-8 N=13
mg/m2
0.40(n=0)n (%)
1.04(n=9)n (%)
1.20(n=4)n (%)
1.38(n=0)n (%)
(n=13)n (%)
CR+PR 0 4 (44) a 2 (50) 0 6 (46) SD 0 1 (11) 0 0 1 (8) PD 0 3 (33) 1 (25) 0 4 (31)
0 1 (11) 1 (25) 0 2 (15) a CR 1
2)
27 20S ChT:T
13 1.20 mg/m2 1 1 1 20S
5% Dixon =0.05
26
1 1 4 8 11 15 18 22 25 1 6 24
20S 2.7.6.2.3-2
20S 2.7.6.2.3-9
20S
20S 1
72 96
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2.7.6 LCCC9834/MSKCC00-31 90
-10
0
10
20
30
40
50
60
70
80
90
100
0 24 48 72 96 120 144 168 192 216 240 264 288 312 336 360 384 408 432 456 480 504 528 552 576 600
hr
20S
%
0.40 mg/m2
1.04 mg/m2
1.20 mg/m2
1.38 mg/m2
1 2 3 4 5 6 7 8
2.7.6.2.3-2 1 1 4 8 11 15 18 22 251 6 24 20S
2.7.6.2.3-9 1 20S
20S (%) 1
(mg/m2) 1 6 24 a 80%
0.40 26 17 5 57 18 0 1.04 62 43 25 81 25 1 1.20 66 52 29 85 25 1 1.38 65 49 37 91 22 4
a 1 20S
1 1 1 Sigmoid Emax
2.7.6.2.3-3
Sigmoid Emax 0.8 mg/m2
ED50 0.46 mg/m2 n=26 n=3
11 20S
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2.7.6 LCCC9834/MSKCC00-31 91
0
10
20
30
40
50
60
70
80
90
100
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4
mg/m2
Emax=68.3±12.2 ED50=0.46 mg/m220
S%
2.7.6.2.3-3 1 20S
(5)
1)
1 1 2 4 1 4 8 11 15 18 22 25
14 17 1 39 42 8
27 2.7.6.2.3-10 27
22.3 mg 3.2 86.5 mg
11 3 32
7 46 1.5 11 5 152
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2.7.6 LCCC9834/MSKCC00-31 92
2.7.6.2.3-10 N=27
mg/m2
0.40(n=3)n (%)
1.04(n=12)n (%)
1.20(n=7)n (%)
1.38(n=5)n (%)
(n=27)n (%)
1 mg/m2 3.2 8.32 9.60 11.04 -
SD 2.7 (0.93) 7.4 (1.40) 7.0 (2.22) 7.9 (2.32) 6.9 (2.29) 3.2 8.3 7.2 6.9 7.2
1.6, 3.2 5.2, 8.4 3.6, 9.6 5.5, 11.1 1.6, 11.1 mg
SD 5.3 (2.23) 27.2 (17.92) 14.3 (5.03) 31.8 (33.40) 22.3 (19.82)5.0 28.3 13.9 12.5 13.9
3.2, 7.6 8.6, 66.2 7.3, 23.2 8.8, 86.5 3.2, 86.5
SD 7 (2.3) 14 (8.7) 6 (2.9) 12 (11.1) 11 (8.1) 8 15 6 5 8
4, 8 5, 32 3, 12 4, 30 3, 32 a
SD 21 (8.4) 63 (46.5) 25 (12.9) 52 (59.7) 46 (42.9) 25 63 22 18 25
11, 26 14, 152 15, 53 11, 152 11, 152 b
SD 0.8 (0.29) 1.8 (1.09) 0.8 (0.37) 1.5 (1.39) 1.4 (1.02) 1.0 1.8 0.8 0.6 1.0
0.5, 1.0 0.6, 4.0 0.4, 1.5 0.5, 3.8 0.4, 4.0 ab 6 8
0.40 mg/m2 1.20 mg/m2 1.38 mg/m2
1.04 mg/m2 1.04 mg/m2 14
0.40 mg/m2 1.20 mg/m2 1.38 mg/m2 7 6 12
1.04 mg/m2 63 0.40 mg/m2 1.20
mg/m2 1.38 mg/m2 21 25 52
1.04 mg/m2 1.8 0.40 mg/m2 1.20 mg/m2 0.8 1.38 mg/m2
1.5
1 2.7.6.2.3-11
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2.7.6 LCCC9834/MSKCC00-31 93
2.7.6.2.3-11 1
(mg/m2) 0.40
(n=3)n (%)
1.04(n=12)n (%)
1.20(n=7)n (%)
1.38(n=5)n (%)
(n=27)n (%)
8 1 (33) 4 (33) 5 (71) 4 (80) 14 (52)
1 0 0 0 1 (20) 1 (4) 2 0 2 (17) 3 (43) 0 5 (19) 3 0 2 (17) 0 2 (40) 4 (15) 4 0 0 1 (14) 1 (20) 2 (7) > 4 1 (33) 0 1 (14) 0 2 (7)
11 (33) 3 (25) 5 (71) 4 (80) 13 (48)
48% 13/27 1 8 1
2 2 0.40 mg/m2 67% 2/3
1.04 mg/m2 67% 8/12 1.20 mg/m2 29% 2/7 1.38 mg/m2 20% 1/5
1 52% 14/27 1
8 57% 8/14 3 15 18
36% 5/14 2 8 11 7% 1/14 4 22
1 1 4
1 8 14 13
1
2)
30
2.7.6.2.3-12
5
2.7.6.2.3-12
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2.7.6 LCCC9834/MSKCC00-31 94
2.7.6.2.3-13 27 1
1 96%
26/27 0.40 mg/m2 1
2.7.6.2.3-13 N=27
mg/m2
0.40 (n=3)
1.04(n=12)
1.20(n=7)
1.38(n=5)
(%) 3 (100) 2 (67) 12 (100) 12 (100) 7 (100) 7 (100) 5 (100) 5 (100)
30 1.20 mg/m2 8 1.04 mg/m2
19 1 29 25
6 1.04 mg/m2 16 1.20 mg/m2
12 1 4
9 1 6 1.04 mg/m2
30 52% 14/27
0.40 mg/m2 33% 1/3 1.04 mg/m2 42% 5/12 1.20 mg/m2 71% 5/7
1.38 mg/m2 60% 3/5 2
33%
9/27 1.04 mg/m2 25% 3/12 1.20 mg/m2 43% 3/7 1.38
mg/m2 60% 3/5 2
2.7.6.2.3-14
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2.7.6 LCCC9834/MSKCC00-31 95
2.7.6.2.3-14N=27
(mg/m2) MedDRA PT (Cycle/Day) Grade
1.04 6 C2 / D20 3 3 C2 /D20 3
17 C1 / D38 2 C2 / D2 3 C2 / D24 2
18 C1 / D7 3 1.20 9 C1 /D7 3
C1 / D14 3 13 C1 / D17 3 14 C2 / D15 3
C2 / D15 4 1.38 10 C1 / D14 3
C2 / D17 3 11 C2 / D24 3
+LD / D16 2 N/A 202 +LD / D1 1 N/A
+LD / D6 3 N/A+LD N/A
Grade3 Grade4
Grade3 2.7.6.2.3-15 Grade3
78% 21/27 0.40 mg/m2 33% 1/3 1.04 mg/m2 67% 8/12
1.20 mg/m2 100% 7/7 1.38 mg/m2 100% 5/5 Grade3
Grade3
63% 17/27 1.04 mg/m2 50% 6/12 1.20 mg/m2
100% 7/7 1.38 mg/m2 80% 4/5 0.40 mg/m2
Grade4 2.7.6.2.3-16 Grade4 27 3 11%
3 1.20 mg/m2 Grade4
8 13 14
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2.7.6 LCCC9834/MSKCC00-31 96
2.7.6.2.3-15 Grade3 N=27
mg/m2
0.40(n=3)
1.04(n=12)
1.20(n=7)
1.38(n=5)
MedDRA/J v8.0 (SOC) (PT)
Grade3 (%) 1 (33) 8 (67) 8 (67) 7 (100) 7 (100) 5 (100) 5 (100)
6 (50) 6 (50) 7 (100) 7 (100) 4 (80) 4 (80) 4 (33) 4 (33) 4 (57) 4 (57) 3 (60) 3 (60) 1 (8) 1 (8) 4 (57) 4 (57) 1 (20) 1 (20) 2 (17) 2 (17) 1 (14) 1 (14) 2 (40) 2 (40) 2 (17) 2 (17) 2 (29) 2 (29) 3 (25) 3 (25) 3 (25) 3 (25) 1 (14) 1 (14) 2 (40) 2 (40) 2 (17) 2 (17) 2 (40) 2 (40) 1 (8) 1 (8) 1 (14) 1 (14) 1 (8) 1 (8) 2 (17) 2 (17) 2 (29) 1 (20) 1 (8) 1 (8) 1 (14) 1 (20) 1 (8) 1 (8) 1 (14) 1 (14) 1 (8) 1 (8) 2 (17) 2 (29) 1 (14)
1 (14) 1 (14)
1 (8) 1 (8) 1 (14) 1 (8) 1 (8) 1 (14) 1 (14) 1 (8) 1 (8) 1 (14) 1 (14) 1 (14) 1 (14) 1 (14) 1 (14) 1 (8) 1 (8) 1 (20) 1 (20) 1 (20) 1 (20) 1 (14) 1 (14) 1 (14)
1 (33) 1 (33)
1 (14) 1 (14) 1 (14) 1 (14) 1 (14) 1 (14) 1 (8) 1 (8) 1 (8) 1 (8) 1 (8) 1 (8)
3 1 (8) 1 (8) 1 (8) 1 (8) 1 (14)
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2.7.6 LCCC9834/MSKCC00-31 97
mg/m2
0.40(n=3)
1.04(n=12)
1.20(n=7)
1.38(n=5)
MedDRA/J v8.0 (SOC) (PT)
1 (14)
2.7.6.2.3-16 Grade4 N=27
mg/m2
0.40(n=3)
1.04(n=12)
1.20(n=7)
1.38(n=5)
MedDRA/J v8.0 (SOC) (PT)
Grade4 (%) 3 (43) 1 (14)
1 (14) 1 (14) 1 (14) 1 (14) 1 (14) 1 (14) 1 (14) 1 (14) 1 (14) 1 (14)
2.7.6.2.3-17
37% 10/27 0.40 mg/m2 33% 1/3 1.04
mg/m2 8% 1/12 1.20 mg/m2 57% 4/7 1.38 mg/m2 80% 4/5
7% 2/27
Grade3 90% 9/10
Grade1 10% 1/10 Grade4
30% 3/10 1.20 mg/m2
Grade4
3 3 8 12 3
8 12
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2.7.6 LCCC9834/MSKCC00-31 98
2.7.6.2.3-17
(mg/m2) MedDRA PT (Cycle/Day) Grade
0.40 3 C1 / D12 3 1.04 6 3 C2 / D20 3
C2 / D20 3 C2 / D21 3 C2 / D21 3
1.20 8 C1 / D22 2 C1 / D29 2 C1 / D29 4
12 C1 / D15 3 C1 / D18 3
13 C1 / D23 1 C1 / D23 3 C1 / D23 4 C1 / D23 3
14 C2 / D15 4 C2 / D15 3
1.38 11 C2 / D24 3 201 C1 / D15 3 202 C1 / D11 1 203 C1 / D11 3
C1 / D12 2
DLT
DLT 2.7.6.2.3-18 DLT Grade3 1.04 mg/m2
1.38 mg/m2 2 4 Grade3 1.04 mg/m2 1.20 mg/m2
1 2 Grade3 1.20 mg/m2 1
DLT
2.7.6.2.3-18 DLT N=27
mg/m2
0.40 (n=3)
1.04(n=12)
1.20(n=7)
1.38(n=5)
(n=27)
DLTn (%)
0 3 (25) 2 (29) 2 (40) 7 (26)
DLT MedDRA PT
0 2 (17) 0 2 (40) 4 (15)
0 1 (8) 1 (14) 0 2 (7) 0 0 1 (14) 0 1 (4)
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2.7.6 LCCC9834/MSKCC00-31 99
2.7.6.2.3-19 27 1
74% 20/27 59% 16/27
56% 15/27 52% 14/27 48% 13/27
0.40 mg/m2 1 96%
26/27
74% 20/27 59% 16/27 52% 14/27
48% 13/27
2.7.6.2.3-19 N=27
mg/m2
0.40(n=3)
1.04(n=12)
1.20(n=7)
1.38(n=5)
MedDRA/J v8.0 (SOC) (PT)
1 3 (100) 2 ( 67) 12 (100) 12 (100) 7 (100) 7 (100) 5 (100) 5 (100)
1 (33) 12 (100) 12 (100) 5 (71) 5 (71) 5 (100) 5 (100) 9 (75) 9 (75) 3 (43) 3 (43) 4 (80) 4 (80) 4 (33) 2 (17) 1 (14) 1 (14) 1 (20) 1 (20) 6 (50) 5 (42) 1 (8) 1 (8) 2 (29) 2 (29) 1 (20) 1 (20) 3 (25) 1 (8) 1 (20)
1 (33) 1 (8) 2 (17) 1 (8) 1 (8) 1 (8) 1 (8) 1 (14) 1 (14) 1 (8) 1 (14) 1 (8) 1 (8)
1 (33) 1 (33) 11 (92) 8 (67) 6 (86) 5 (71) 4 (80) 4 (80) 6 (50) 5 (42) 4 (57) 4 (57) 4 (80) 4 (80)
1 (33) 1 (33) 5 (42) 4 (33) 2 (29) 2 (29) 2 (40) 2 (40) 5 (42) 2 (17) 2 (29) 1 (14) 2 (40) 2 (40) 4 (33) 3 (25) 2 (29) 2 (29) 2 (40) 1 (20) 2 (17) 1 (8) 1 (14) 2 (40) 2 (40) 3 (25) 1 (8) 1 (8) 1 (20) 1 (8) 1 (20) 1 (8) 1 (8) 1 (14) 1 (14) 1 (8) 1 (14) 1 (20) 1 (8) 1 (8) 1 (20) 1 (8) 1 (8) 1 (14)
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2.7.6 LCCC9834/MSKCC00-31 100
mg/m2
0.40(n=3)
1.04(n=12)
1.20(n=7)
1.38(n=5)
MedDRA/J v8.0 (SOC) (PT)
11 (92) 11 (92) 7 (100) 7 (100) 4 (80) 4 (80) 9 (75) 9 (75) 7 (100) 7 (100) 4 (80) 4 (80) 7 (58) 6 (50) 5 (71) 5 (71) 3 (60) 3 (60) 7 (58) 7 (58) 4 (57) 4 (57) 2 (40) 2 (40) 5 (42) 5 (42) 3 (43) 3 (43) 2 (40) 2 (40) 4 (33) 4 (33) 1 (14)
1 (33) 1 (33) 11 (92) 10 (83) 5 (71) 4 (57) 4 (80) 2 (40) 8 (67) 7 (58) 2 (29) 2 (29) 2 (40) 1 (20) 3 (25) 2 (17) 2 (29) 2 (29) 2 (17) 1 (8) 1 (14) 1 (14) 2 (40) 1 (20) 1 (8) 1 (8) 1 (14) 1 (14) 1 (20) 1 (8) 1 (14) 1 (14)
1 (33) 1 (33) 1 (14) 1 (14) 1 (8) 1 (8) 1 (8) 1 (8) 1 (8) 1 (14) 1 (8) 1 (8) 1 (8) 1 (8)
1 (33) 1 (8)
1 (33) 9 (75) 5 (42) 3 (43) 2 (29) 4 (80) 1 (20) 5 (42) 1 (8) 1 (14) 1 (20) 2 (17) 2 (17) 1 (14) 1 (14) 1 (20) 1 (8) 1 (8) 2 (40) 1 (20) 3 (25) 2 (17) 1 (8) 2 (17)
1 (33) 1 (8) 1 (8) 1 (8) 1 (8) 1 (14) 1 (14) 1 (8) 1 (14) 1 (14)
1 (33) 8 (67) 3 (25) 5 (71) 1 (14) 3 (60) 4 (33) 2 (17) 2 (29) 1 (14) 1 (20) 2 (17) 1 (8) 1 (14) 1 (20) 2 (17) 1 (8) 1 (20) 1 (8) 1 (8) 1 (14) 1 (20) 2 (17) 1 (8) 1 (14) 1 (8) 1 (14)
1 (33) 1 (14) 2 (17) 2 (17) 1 (20) 1 (14) 1 (8)
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2.7.6 LCCC9834/MSKCC00-31 101
mg/m2
0.40(n=3)
1.04(n=12)
1.20(n=7)
1.38(n=5)
MedDRA/J v8.0 (SOC) (PT)
1 (20) 1 (8) 1 (8) 1 (8) 1 (8) 1 (14) 1 (8) 1 (20) 8 (67) 6 (50) 4 (57) 3 (43) 3 (60) 3 (60) 4 (33) 4 (33) 1 (14) 1 (14) 2 (40) 2 (40) 2 (17) 1 (8) 2 (29) 2 (29) 1 (20) 4 (33) 3 (25) 1 (20) 1 (20) 2 (17) 1 (8) 2 (40) 2 (40) 2 (17) 2 (17) 1 (14) 1 (14) 1 (20) 1 (8) 1 (8) 1 (14) 1 (14) 1 (20) 1 (14) 1 (14) 1 (20) 1 (20) 1 (8) 1 (8) 1 (8) 1 (8) 1 (20) 1 (20) 1 (8) 1 (8) 7 (58) 6 (50) 4 (57) 1 (14) 2 (40) 2 (40)
3 (25) 3 (25) 1 (20) 1 (20) 2 (17) 1 (14) 1 (14)
2 (17) 1 (8) 1 (14) 1 (14) 2 (17) 2 (17) 1 (20) 1 (20) 1 (8) 1 (8) 2 (29)
1 (8) 1 (8)
1 (14) 1 (14)
1 (8) 1 (8) 1 (14) 1 (14) 1 (8) 1 (8) 1 (14) 1 (8) 1 (8) 1 (14) 1 (8) 1 (8) 1 (8)
1 (8) 1 (8)
1 (8) 1 (8) 1 (8) 1 (8) 6 (50) 5 (42) 2 (29) 1 (14) 4 (33) 3 (25) 3 (25) 1 (8) 2 (17) 1 (8) 1 (14) 1 (14) 1 (14) 1 (8) 1 (8) 1 (8)
1 (33) 5 (42) 2 (17) 2 (29) 2 (29)
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2.7.6 LCCC9834/MSKCC00-31 102
mg/m2
0.40(n=3)
1.04(n=12)
1.20(n=7)
1.38(n=5)
MedDRA/J v8.0 (SOC) (PT)
2 (17) 2 (17) 1 (14) 1 (14) 2 (17) 1 (8) 1 (8) 1 (14) 1 (14) 1 (8) 1 (8) 1 (8) 1 (8)
1 (33) 1 (8) 1 (8) 1 (8) 1 (8) 1 (8) 1 (8) 3 (25) 1 (8) 3 (43) 1 (20) 1 (8) 1 (8) 1 (20) 1 (14) 1 (14) 1 (14) 1 (8) 1 (8) 1 (8) 1 (14) 1 (8) 1 (14)
1 (33) 2 (17) 1 (14) 2 (40) 1 (20) 1 (14) 1 (8)
1 (33) 1 (14) 1 (20) 1 (20) 1 (20) 1 (8)
1 (33) 3 (25) 1 (8) 1 (20) 1 (20) 1 (33) 2 (17) 1 (8)
1 (8) 1 (8) 1 (20) 1 (20) 1 (8) 3 (25) 1 (20) 2 (17) 1 (8) 1 (8) 1 (20) 3 (25) 2 (17) 1 (14) 1 (8) 1 (8) 1 (14) 1 (8) 1 (8) 1 (8)
2 (17) 1 (8)
1 (8) 1 (8) 1 (8)
1 (8) 1 (14)
1 (14) 1 (8)
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2.7.6 LCCC9834/MSKCC00-31 103
mg/m2
0.40(n=3)
1.04(n=12)
1.20(n=7)
1.38(n=5)
MedDRA/J v8.0 (SOC) (PT)
1 (14) 1 (14) 1 (14) 1 (14) 1 (14) 1 (14) 1 (8) 1 (8) 1 (8) 1 (8) 1 (8) 1 (8)
3 1 (8) 1 (8) 1 (8) 1 (8)
Grade3
Grade3 0.40 mg/m2 0% 0/3 1.04
mg/m2 33% 4/12 1.20 mg/m2 57% 4/7 1.38 mg/m2 60% 3/5
Grade4 Grade3 6
2 Grade3
1 Grade3 1
59% 16/27 0.40 mg/m2 0% 0/3 1.04 mg/m2
75% 9/12 1.20 mg/m2 43% 3/7 1.38 mg/m2 80% 4/5
16 1
Grade1 2 Grade3 1.20 mg/m2
1 Grade2 1.38 mg/m2 1 Grade2
52% 14/27 0.40 mg/m2 0% 0/3 1.04 mg/m2
50% 6/12 1.20 mg/m2 57% 4/7 1.38 mg/m2 80% 4/5
1.04 mg/m2 1 13
1.38 mg/m2 1 Grade2 Grade1
14 12 1 2 2
1.04 mg/m2 4 1.20 mg/m2 1.38 mg/m2 2 8
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2.7.6 LCCC9834/MSKCC00-31 104
20S
20S 2.7.6.2.3-20
27 26 20S
26 20S 80% 7 80% 90%
15 90% 4
DLT Grade3
20S 90% 90%
2.7.6.2.3-20 20S
20S (%) <80
(n=7)80 <90
(n=15)90
(n=4) (n=26)DLT
N (%) 2 (29) 3 (20) 2 (50) 7 (27) 90% a 5, 66 6, 44 10, 90 13, 45
Grade3 N (%) 4 (57) 11 (73) 4 (100) 19 (73) 90% a 23, 87 49, 90 47, 100 55, 87
N (%) 3 (43) 6 (40) 4 (100) 13 (50) 90% a 13, 77 19, 64 47, 100 33, 67
N (%) 2 (29) 5 (33) 2 (50) 9 (35) 90% a 5, 66 14, 58 10, 90 19, 53
a
(i)
1 2.7.6.2.3- 4
0.40 1.04 1.38 mg/m2 187 224 224 109 /L
UNC 150 440 109 /L MSKCC 160 440 109 /L 0.40
1.04 1.38 mg/m2 8
15 22
1.20 mg/m2 115
109 /L
1.04 mg/m2 2.7.6.2.3-5 1.04 mg/m2
MTD 63 2.7.6.2.3-10
N=27
1.04 mg/m2 3
1
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2.7.6 LCCC9834/MSKCC00-31 105
2.7.6.2.3- 4 1
2.7.6.2.3-5 1.04 mg/m2
109 /L
UNC
109 /L
0.40 mg/m2
1.04 mg/m2
1.20 mg/m2
1.38 mg/m2
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2.7.6 LCCC9834/MSKCC00-31 106
1 2.7.6.2.3-6
0.40 1.04 1.20 1.38 mg/m2 122 109 103 122 g/L
18 135 175 g/L
1
19% 5/27 Grade3
2.7.6.2.3-6 1
1 2.7.6.2.3-7
0.40 1.04 1.38 mg/m2 7.8 5.4 8.6 109 /L
4.5 11.0 109 /L 1.20 mg/m2 4.4
109 /L 0.40 1.04 1.20 mg/m2 1
15 22
1.38 mg/m2 1
22
1 201 1 22
18.4 40.8 109 /L
1
37% 10/27 1 Grade3 26%
7/27 Grade3
18
g/L
0.40 mg/m2
1.04 mg/m2
1.20 mg/m2
1.38 mg/m2
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2.7.6 LCCC9834/MSKCC00-31 107
2.7.6.2.3-7 1
(ii)
DLT
1 2.7.6.2.3-8
0.40 1.04 1.20 1.38 mg/m2 139 137 139 138 mmol/L
UNC 135 145 mmol/L MSKCC 136 144 mmol/L 0.40
1.04 1.20 mg/m2 1
3
1.04 mg/m2 2 17 207
1 Grade3 DLT 1.38 mg/m2
8 8 15
22
2 10 202 1 Grade3
10 126 mmol/L 202 121 mmol/L DLT
109 /L
0.40 mg/m2
1.04 mg/m2
1.20 mg/m2
1.38 mg/m2
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2.7.6 LCCC9834/MSKCC00-31 108
2.7.6.2.3-8 1
1 2.7.6.2.3-9
0.40 1.04 1.20 1.38 mg/m2 4.4 4.0 4.0 4.3 mmol/L
UNC 3.5 5.0 mmol/L MSKCC 3.5 5.1 mmol/L
1.04 mg/m2 1 18 1.20 mg/m2 1
13 2 Grade3 1 DLT
mm
ol/L
UNC
0.40 mg/m2
1.04 mg/m2
1.20 mg/m2
1.38 mg/m2
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2.7.6 LCCC9834/MSKCC00-31 109
2.7.6.2.3-9 1
2.7.6.2.3.3
2 4 1 4 8 11 15 18 22 25 14 17
MTD 1.04 mg/m2
1 DLT Grade3 4 Grade3
2 Grade3 1
Grade3
20S
Sigmoid Emax 20S
20S
1 72 96
1.04 mg/m2 5 1
mm
ol/L
0.40 mg/m2
1.04 mg/m2
1.20 mg/m2
1.38 mg/m2
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2.7.6 LCCC9834/MSKCC00-31 110
2
2 4 1 4 8 11 15 18 22 25 14 17
5 52% 14/27 1 8
14
8 3
5
2 2 1 2