ボルテゾミブ 2.7.5 参考文献 1

2.7.5 参考文献

(1) 「2.7.1 生物薬剤学及び関連する分析法の概要」の参考文献

1) Lightcap ES, McCormack TA, Pien CS, Chau V, Adams J, Elliott PJ. Proteasome inhibition

measurements: clinical application. Clinical Chemistry 2000; 46 (5):673-83.

2) Elliott PJ, Soucy TA, Pien CS, Adams J, Lightcap ES. Assays for Proteasome Inhibition.

Meth Mol Med 2003;85:163-72.

(2) 「2.7.2 臨床薬理の概要」の参考文献

該当資料なし。

(3) 「2.7.3 臨床的有効性の概要」の参考文献

1) Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, et al. Criteria for evaluating

disease response and progression in patients with multiple myeloma treated by high-dose therapy and

haemopoietic stem cell transplantation. Myeloma. Subcommittee of the EBMT. European Group for

Blood and Marrow Transplant. Br J Haematol 1998; 102 (5):1115-23.

2) Southwest Oncology Group Statistical Center: Statistical Designs and Study Monitoring Policy （July

2002）.

3) Alexanian R, Barlogie B, Dixon D. High-dose glucocorticoid treatment of resistant myeloma. Ann

Intern Med 1986; 105 (1):8-11.

4) O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979; 35

(3):549-56.

5) Fleiss JL. Statistical Methods for Rates and Proportions. 2nd ed. New York: John Wiley & Sons.;

1981.

6) Kumar SK, Therneau TM, Gertz MA, Lacy MQ, Dispenzieri A, Rajkumar SV, et al. Clinical course of

patients with relapsed multiple myeloma. Mayo Clin Proc 2004; 79(7):867-74.

(4) 「2.7.4 臨床的安全性の概要」の参考文献

1) Kumar SK, Therneau TM, Gertz MA, Lacy MQ, Dispenzieri A, Rajkumar SV, et al. Clinical course of

patients with relapsed multiple myeloma. Mayo Clin Proc 2004; 79(7):867-74.

2) Phillips EJ, Feld R, McGeer A. Infections in myeloma. In: Malpas JS, Bergsagel DE, Kyle RA,

Anderson KC, editors. Myeloma: Biology and Management. 2nd ed.: Oxford University Press; 1998.

p.436-76.

ボルテゾミブ 2.7.5 参考文献 2

3) Mast A. Barnes-Jewish Hospital Laboratory Reference Values. In: Carey CF, Lee HH, Woeltje KF,

editors. The Washington Manual of Medical Therapeutics. 29th ed. Philadelphia, PA:

Lippincott-Raven Publishers; 1998. p.527-33.

������ 2.7.6� ��� ��

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2.7.6.1 �������..............................................................................................................1

2.7.6.2 ����� ..........................................................................................................5

2.7.6.2.1 ����������DM98-194 � !" 5.3.5.2.6#.........................................................5

2.7.6.2.2 ����������98-104A � !" 5.3.5.2.7#..........................................................47

2.7.6.2.3 ����������LCCC9834/MSKCC00-31 � !" 5.3.5.3.1#...............................81

2.7.6.2.4 ����������M34100-027 � !" 5.3.4.2.5# ................................................. 111

2.7.6.2.5 ��$%&�����M34103-058 '(!" 5.3.4.2.8# ................................................. 153

2.7.6.2.6 �����)����M34101-039 '(!" 5.3.5.1.1# ................................................. 163

2.7.6.2.7 �*��/+����JNJ-26866138-JPN-MM-101 '(!" 5.3.5.2.1# .......................... 274

2.7.6.2.8 �����+����M34100-024 '(!" 5.3.5.2.3# ................................................. 317

2.7.6.2.9 �����+����M34100-025 '(!" 5.3.5.2.4# ................................................. 366

2.7.6.2.10 �����+����M34101-029 '(!" 5.3.5.2.5# ................................................. 426

2.7.6 1

2.7.6

2.7.6.1

2.7.6 2

[]

ID

M98

-194

[5.3

.5.2

.6]

DLT

MTD

PKPD

0.13

2.00

mg/

m2

11

14

13

5

5415

a

I98

-104

A

[5.3

.5.2

.7]

DLT

MTD

PD

0.13

1.56

mg/

m2

11

22

10

3

436

a

ILC

CC

9834

/

MSK

CC

00-3

1

[5.3

.5.2

.8]

DLT

MTD

PD

0.40

1.38

mg/

m2

11

24

1417

6

27

[]

4a

IM

3410

0-02

7

[5.3

.4.2

.5]

DLT

MTD

PK

PD

1.0

1.3

mg/

m2

11

22

10

3 500

800

1000

mg/

m2

11

12

13

3

318

a

2.7.6 3

[]

M34

103-

058

[5.3

.4.2

.8]

PK

PD

1.0

1.3

mg/

m2

11

22

10

3

418

III

M34

101-

039

[5.3

.5.1

.1]

1.3

mg/

m2

11

22

10

3 11

14

13

5

40 m

g/

11

14

912

1720

155

11

14

244

669

333

336

11

(3 8 5 3)

9

(5 4 4 5)

I/II

JNJ-

2686

6138

-JPN

-

MM

-101

[5.3

.5.2

.1]

DLT

PK

PDa

0.7

1.0

1.3

mg/

m2

11

22

10

3

166

aI

2.7.6 4

[]

IIM

3410

0-02

4

[5.3

.5.2

.3]

1.0

1.3

mg/

m2

1.0

1.3

mg/

m2

11

22

10

3

548

IIM

3410

0-02

5

[5.3

.5.2

.4]

1.3

mg/

m2

11

22

10

3

202

8

IIM

3410

1-02

9

[5.3

.5.2

.5]

1.0

mg/

m2

1.3

mg/

m2

11

22

10

3 11

14

13

5

63

(M34

100-

024

M34

100-

025

)

24a

(32

)

a

2.7.6 DM98-194 5

2.7.6.2

2.7.6.2.1 DM98-194 5.3.5.2.6

2.7.6.2.1.1

2.7.6.2.1-1

2.7.6.2.1-1

DM98-194Papandreou CN, Daliani D, Nix D, Yang H, Madden T, Wang X, et al. Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol. 2004 Jun 1;22 (11): 2108-21.

Logothetis CJ, Yang H, Daliani D, Millikan RE, Tu S-M, Pagliaro L, et al. Dose Dependent Inhibition of 20S Proteasome Results in Serum Il-6 and PSA Decline in Patients (PTS) with Androgen-Independent Prostate Cancer (AI PCa) Treated with the Proteasome Inhibitor PS-341. Abstract 740. 37th Annual Meeting of the American Society of Clinical Oncology, May 2001, San Francisco, CA.

Papandreou C, Daliani D, Millikan RE, Tu S-M, Pagliaro L, Adams J, et al. Phase I Study of Intravenous (I.V.) Proteasome Inhibitor PS-341 in Patients (Pts) with Advanced Malignancies. Abstract 340. 37th Annual Meeting of the American Society of Clinical Oncology, May 2001, San Francisco, CA.

Nix D, Pien C, Newman R, Madden T, Felix E, Adams J, Elliott P. Clinical Development of a Proteasome Inhibitor, PS-341, for the Treatment of Cancer. Abstract 339. 37th Annual Meeting of the American Society of Clinical Oncology, May 2001, San Francisco, CA. Papandreou P, Pagliaro L, Millikan R, Daliani D, Herrmann J, Yang H, et al. Phase I Study of PS-341, a Novel Proteasome Inhibitor, in Patients with Advanced Malignancies. Abstract 738. 36th Annual Meeting of the American Society of Clinical Oncology, May 2000, New Orleans, LA.

Elliot P, Pien CS, Papandreou CN, Smith MR, Newman R, Millikan RE, et al. PS-341: Clinical Development of the First Proteasome Inhibitor. Abstract Number NA. 35th AnnualMeeting of the American Society of Clinical Oncology, May 1999, Atlanta, GA.

1 4 2DLT MTD

1 4 220S

20S

2.7.6 DM98-194 6

1)2)183) Zubrod 24)35) 14

3,000 /mm3

1,500 /mm3

100,000 /mm3

SGOT AST N 2.5 NSGPT ALT N 2.5

1.5 mg/dL 50 mL/min

6) 50%7)

1) 22) 123) 12 -894) 45) 46)7)

222

8) 2

9)10)11)512) X

13)

MTD 220 MTD 15

54

DLT 1 Grade4 Grade3 Grade3

MTD DLT 25%

2.7.6 DM98-194 7

191 mL 0.5 mg 2 mL

2.5 mg 25 mg1 0.13 0.25 0.40 0.60 0.75 0.80 0.85 0.90 1.00 1.10 1.21 1.32

1.45 1.60 1.80 2.00 2.20 2.42 2.66 2.95 mg/m2

0.13 2.00 mg/m2

1 1 1 4 1 8 15 22 135 1 2 CRPR SD

0.13 mg/m2 2 1MPI

Continual Reassessment Method CRM CRM

141 Day1 8 15 22

123 2 Day1, 8, 15

22 1

20S

ITT Intent-To-Treat

ZubrodX

0.13 2.00 mg/m2 16

70.13 0.60 mg/m2 0.75 0.90 mg/m2 1.00 1.32 mg/m2 1.45 mg/m2 1.60

mg/m2 1.80 mg/m2 2.00 mg/m2

SAS ver. 8.2

1

2.7.6 DM98-194 8

1920

2.7.6.2.1.2

(1)

MD Anderson Cancer Center MDACC 54

1 048

53 0.13 2.00 mg/m2 16 1

2.7.6.2.1-2

2.7.6.2.1-2

mg/m2N

mg/m2 N

0.13 4 001 002 003 0040.25 2 005 0060.40 2 007 008

0.13 0.60

10

0.60 2 009 0100.75 2 011 0120.80 3 013 014 0150.85 2 016 017

0.75 0.90

9

0.90 2 018 0191.00 2 020 0211.10 2 022 0231.21 2 024 025

1.00 1.32

8

1.32 2 026 0271.45 6 1.45 6 028 029 032 033 034 0351.60 13 1.60 13 030 031 036 037 038 039 040

041 042 043 044 045 0461.80 2 1.80 2 047 0492.00 5 2.00 5 050 051 052 053 054

DLT

2.7.6 DM98-194 9

0.13 1.60 mg/m2 1.60 mg/m2 2

1 DLT 031 Grade3 1

1.45 mg/m2 4 1.45 mg/m2 DLT

1.60 mg/m2 11 11 2 DLT

041 Grade3 045 Grade3 1.60 mg/m2 DLT 23%

3/13 6 17% 1/6 1.60 mg/m2 13

1.80 mg/m2 1.80 mg/m2 2 1

DLT 047 Grade3 MPI

2.00 mg/m2 2.00 mg/m2 5 2 DLT

053 Grade 3 054 Grade 3

2.00 mg/m2 5 20S

MTD DLT 25% 1.60 mg/m2

6 DLT 17% 1 4

1 8 15 22 13 MTD

1.60 mg/m2

2.7.6.2.1-1 1 53

ITT

54

1

ITT

53

2.7.6.2.1-1

2.7.6 DM98-194 10

(2)

2.7.6.2.1-3 2

55% 29/53 2.00 mg/m2 20%

50 100%

45% 24/53 2 63%

15/24 29% 7/24 8% 2/24

2.7.6.2.1-3

mg/m2

0.130.60

n (%)

0.750.90n (%)

1.001.32

n (%)

1.45n (%)

1.60n (%)

1.80n (%)

2.00n (%) n (%)

a 10 9 8 6 13 3 5 54 b 5(50) 5(56) 4(50) 3(50) 9(69) 2(100) 1(20) 29(55)

5(50) 4(44) 4(50) 3(50) 4(31) 0 4(80) 24(45)

5(100) 4(100) 3(75) 2(67) 0 0 1(25) 15(63) 0 0 0 1(33) 4(100) 0 2(50) 7(29) 0 0 1(25) 0 0 0 1(25) 2(8)

a 1.8 mg/m2 1 048b 2 1 2 4

2 035 052

(3)

53 2.7.6.2.1-4

96% 51/53 92% 49/53 65.5 45

78 Zubrod 12 56%

23/41 0 1 34% 14/41 2 10% 4/41

2.7.6 DM98-194 11

2.7.6.2.1-4 N=53

(mg/m2)0.130.60

(n=10)

0.750.90(n=9)

1.001.32(n=8)

1.45(n=6)

1.60(n=13)

1.80(n=2)

2.00(n=5) (n=53)

n (%) 9 (90) 8 (89) 8 (100) 6 (100) 13 (100) 2 (100) 5 (100) 51 (96)1 (10) 1 (11) 0 0 0 0 0 2 (4)

n (%) 9 (90) 9 (100) 8 (100) 5 (83) 11 (85) 2 (100) 5 (100) 49 (92)

0 0 0 1 (17) 2 (15) 0 0 3 (6) 1 (10) 0 0 0 0 0 0 1 (2)

( ) N 10 9 8 6 13 2 5 53

(SD) 63.9

(6.95)65.3

(8.59)64.0

(9.59)63.7

(5.13)63.6

(6.58)71.0(9.9)

67.0(8.46)

65.5(7.4)

64.0 67.0 66.5 61.5 65.0 71.0 70.0 65.0 52,73 51,78 45,77 58,71 52,73 64,78 53,75 45,78

(kg) N 10 9 8 6 13 2 5 53

(SD) 87.7

(16.5)96.5

(19.2)77.6

(12.1)80.5

(12.0)92.8

(17.6)90.0

(28.3)100.6(15.6)

89.4(17.3)

85.6 93.0 77.0 79.7 87.1 90.0 100.4 88.4 60,121 61,125 64,94 68,98 67,127 70,110 85,124 60,127

(cm) N 9 9 8 6 12 2 5 51

(SD) 175(7.5)

180(11.6)

179(7.0)

177(4.3)

175(5.8)

173(3.5)

185(6.1)

178(8.0)

178 178 181 175 174 173 188 176 165,185 157,194 170,188 173,184 167,186 170,175 177,193 157,194

BSA (m2)a N 9 9 8 6 12 2 5 51

(SD) 2.0

(0.17)2.1

(0.23)2.0

(0.19)2.0

(0.14)2.0

(0.16)2.0

(0.21)2.2

(0.16)2.0

(0.19)2.0 2.1 2.0 2.0 2.0 2.0 2.3 2.0

1.7,2.2 1.6,2.4 1.7,2.2 1.8,2.1 1.8,2.3 1.8,2.1 2.0,2.4 1.6,2.4(Zubrod) b

0 7 (70) 6 (75) 1 (20) 2 (67) 5 (50) 0 2 (50) 23 (56)1 2 (20) 2 (25) 3 (60) 1 (33) 3 (30) 1 (100) 2 (50) 14 (34)2 1 (10) 0 1 (20) 0 2 (20) 0 0 4 (10)

0 1 3 3 3 1 1 12 ab 1 1

53 2.7.6.2.1-5

91% 48/53

6% 3/53 2% 1/53 2% 1/53

6.2 1.3 18.0

100% 53/53 1 4.3

1 10

57% 30/53 47%

25/53 62% 33/53 62% 33/53

2.7.6 DM98-194 12

57% 30/53 47% 25/53 28% 15/53

23% 12/53 19% 10/53 53%

28/53 17% 9/53 13% 7/53

23% 12/53

2.7.6.2.1-5 N=53

(mg/m2)0.130.60

(n=10)

0.750.90(n=9)

1.001.32(n=8)

1.45(n=6)

1.60(n=13)

1.80(n=2)

2.00(n=5) (n=53)

n (%) 8 (80) 8 (89) 8 (100) 5 (83) 12 (92) 2 (100) 5 (100) 48 (91) 1 (10) 1 (11) 0 1 (17) 0 0 0 3 (6) 1 (10) 0 0 0 0 0 0 1 (2)

0 0 0 0 1 (8) 0 0 1 (2)

N 10 9 8 5 13 2 5 52

(SD) 5.8

(3.38)6.1

(2.64)6.1

(3.23)7.1

(2.43)6.4

(4.25)8.2

(6.36)5.0

(2.63)6.2

(3.32)5.7 6.0 6.2 7.8 6.0 8.2 3.8 5.9

2.1,13.3 1.8,9.1 1.4,9.9 3.6,10.0 1.3,18.0 3.7,12.7 3.4,9.7 1.3,18.0n (%)

5 1 (13) 0 0 1 (20) 0 0 0 2 (4) 6 3 (38) 1 (13) 0 1 (20) 2 (18) 0 2 (50) 9 (20) 7 0 1 (13) 1 (13) 1 (20) 5 (45) 0 0 8 (17) 8 0 2 (25) 4 (50) 1 (20) 2 (18) 1 (50) 0 10 (22) 9 3 (38) 4 (50) 3 (38) 1 (20) 2 (18) 0 0 13 (28) 10 1 (13) 0 0 0 0 1 (50) 2 (50) 4 (9)

2 1 0 1 2 0 1 7 n (%) 9 (90) 9 (100) 6 (75) 5 (83) 13 (100) 1 (50) 5 (100) 48 (91)

N 10 9 8 6 13 2 5 53

(SD) 3.9

(1.66)5.0

(2.45)4.0

(2.88)4.0

(2.1)4.6

(2.1)5.5

(3.54)3.8

(2.68)4.3

(2.24)3.5 5.0 3.5 3.5 5.0 5.5 4.0 4.0 2,7 1,8 1,10 2,7 1,8 3,8 1,8 1,10

( 10%) n(%) 7 (70) 8 (89) 8 (100) 4 (67) 12 (92) 2 (100) 4 (80) 45 (85) 6 (60) 5 (56) 4 (50) 4 (67) 8 (62) 1 (50) 2 (40) 30 (57) 2 (20) 7 (78) 3 (38) 0 9 (69) 1 (50) 3 (60) 25 (47) 9 (90) 7 (78) 5 (63) 6 (100) 10 (77) 2 (100) 3 (60) 42 (79) 5 (50) 5 (56) 5 (63) 5 (83) 9 (69) 2 (100) 2 (40) 33 (62) 6 (60) 5 (56) 5 (63) 4 (67) 8 (62) 2 (100) 2 (40) 33 (62) 7 (70) 3 (33) 5 (63) 3 (50) 7 (54) 2 (100) 3 (60) 30 (57) 4 (40) 3 (33) 4 (50) 4 (67) 8 (62) 1 (50) 1 (20) 25 (47) 4 (40) 2 (22) 4 (50) 1 (17) 4 (31) 0 0 15 (28) 3 (30) 0 2 (25) 3 (50) 2 (15) 1 (50) 1 (20) 12 (23) 4 (40) 1 (11) 1 (13) 1 (17) 1 (8) 1 (50) 1 (20) 10 (19) 5 (50) 7 (78) 6 (75) 5 (83) 9 (69) 2 (100) 4 (80) 38 (72) 3 (30) 6 (67) 3 (38) 3 (50) 8 (62) 1 (50) 4 (80) 28 (53) 2 (20) 3 (33) 0 1 (17) 2 (15) 1 (50) 0 9 (17) 2 (20) 2 (22) 1 (13) 0 2 (15) 0 0 7 (13) 4 (40) 4 (44) 5 (63) 1 (17) 5 (38) 0 1 (20) 20 (38) 3 (30) 3 (33) 3 (38) 1 (17) 1 (8) 0 1 (20) 12 (23) 2 (20) 1 (11) 0 1 (17) 1 (8) 0 1 (20) 6 (11)

0 1 (11) 0 1 (17) 3 (23) 1 (50) 0 6 (11)

2.7.6 DM98-194 13

(4)

1)

2.7.6.2.1-6

2

2.7.6.2.1-6

CR

4

PR 2 50%

4 50%

SD 2 50%

50% 50%

50%

PD 2 50%

50%

PSA

PSA 82% 28/34

PSA 18% 6/34 PSA

1.00 1.32 mg/m2 20% 1/5 1.60 mg/m2 50% 4/8 2.00 mg/m2 20%

1/5

ITT 53 2.7.6.2.1-7

75% 36/48 PD 0.13 0.60 mg/m2 90% 9/10 0.75

0.90 mg/m2 88% 7/8 1.00 1.32 mg/m2 100% 6/6 1.45 mg/m2 80% 4/5

1.60 mg/m2 54% 7/13 1.80 mg/m2 50% 1/2 2.00 mg/m2 50% 2/4

2.7.6.2.1-7 ITT N=53

(mg/m2)0.130.60

(n=10)

0.750.90(n=9)

1.001.32(n=8)

1.45(n=6)

1.60(n=13)

1.80(n=2)

2.00(n=5) (n=53)

PD n (%) 9 (90) 7 (88) 6 (100) 4 (80) 7 (54) 1 (50) 2 (50) 36 (75) 1 (10) 1 (12) 0 1 (20) 6 (46) 1 (50) 2 (50) 12 (25)

0 1 2 1 0 0 1 5

2.7.6 DM98-194 14

2)

PK

1.45,

1.60, 1.80 2.00 mg/m2 24 n=4, 13, 2 5

1 1 PK

2.7.6.2.1-2

2.7.6.2.1-8 1.60 mg/m2

2-

2.7.6.2.1-3 2.7.6.2.1-9

2-

1.60 mg/m2 t1/2 30

t1/2 8.50

C0 11.2 ng/mL 1.80 mg/m2 80.4

ng/mL 1.45 mg/m2 AUC 50.4 ng

hr/mL 1.45 mg/m2 77.0 ng hr/mL 2.00 mg/m2

Vz 721 1270 L Vss 416 979 L

t1/2 8.68 14.8

(hr) 0 5 10 15 20 25

ng/m

L

0.1

1

10

100

1.45 mg/m2 (n=4)1.60 mg/m2 (n=13)1.80 mg/m2 (n=2)2.00 mg/m2 (n=5)

2.7.6.2.1-2 +/-SD n=24

2.7.6 DM98-194 15

2.7.6.2.1-8 n=24

mg/m2 nC0

a)

(ng/mL)AUC(0→24)(ng·hr /mL)

t1/2

(hr)AUC

(ng·hr/mL) VSS

(L)Vz

(L)CL

(L/hr)1.45 4 80.4 43.8 8.68 50.4 416 721 75.3

SD 72.5 20.8 4.16 24.5 158 155 51.2 1.60 13 43.7 39.3 11.9 57.4 696 969 112

SD 78.6 18.6 10.4 47.6 431 473 126 1.80 2 11.2 48.4 10.4 56 711 1030 65.7

SD ND ND ND ND ND ND ND 2.00 5 36 55.3 14.8 77.0 979 1270 63.7

SD 24.2 19.4 4.96 27.7 357 435 29.8 NDa) 0

0.1

1.0

10.0

100.0

0 5 10 15 20 25

hr

ng/m

L

2.7.6.2.1-3 1.60 mg/m2

n=13 2-

2.7.6.2.1-9 1.60 mg/m2

n=13 2-

3.36 mg C0 32.6 ng/mL

t1/2α 0.237 hr t1/2 8.50 hr CL 87.6 L/hr Vss 813 L

AUC(0→t) 41.1 ng hr/mL

2.7.6 DM98-194 16

3)

PD 45 1 1, 8, 15 22

20S ChT:T 2.7.6.2.1-4

0.13 0.60 mg/m2 20S

0.75 2.00 mg/m2

20S

0.13 0.60 mg/m2

20S 1 24

50% 20S

20S

%

Dose 1 Dose 2 Dose 3 Dose 4

-15

-10

-5

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

0.13 0.60 mg/m2

0.75 0.90 mg/m2

1.00 1.32 mg/m2

1.45 mg/m2

1.60 mg/m2

1.80 mg/m2

2.00 mg/m2

1 2 3 4

2.7.6.2.1-4 1 20S0.13 0.60 mg/m2 n=3 5, 0.75 0.90 mg/m2 n=7 9, 1.00 1.32 mg/m2 n=5

8, 1.45 mg/m2 n=6, 1.60 mg/m2 n=11 13, 1.80 mg/m2 n=2, 2.00 mg/m2 n=2

1 1 20S ChT:T

43 Sigmoid Emax

2.7.6.2.1-5

Emax 1.30 mg/m2

50% ED50 0.89 mg/m2 Emax 92%

2.7.6 DM98-194 17

0

10

20

30

40

50

60

70

80

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 (mg/m2)

20S

()

2.7.6.2.1-5 1 20S n=43

1.45 2.00 mg/m2 21

20S ChT:T 2.7.6.2.1-6

20S Simple Emax

Emax 3 ng/mL EC50 1.48 ng/mL

20S 80 %

2.7.6.2.1-6 20S n=21

PS-341 (ng/mL)0 1 2 3 4 5 6 7 8

0

10

20

30

40

50

60

70

80

90

10016

20S

24

JNJ-26866138 ng/mLng/mL

2.7.6 DM98-194 18

(5)

1)

1 1 1 4 1 8 15 22 13 5

1 4 4 13

53 2.7.6.2.1-10

2.7.6.2.1-10 N=53

(mg/m2)0.130.60

(n=10)

0.750.90(n=9)

1.001.32(n=8)

1.45(n=6)

1.60(n=13)

1.80(n=2)

2.00(n=5) (n=53)

mg N 10 9 8 6 13 2 5 53

(SD) 8.3

(14.3)18.4

(16.2)17.5

(11.2) 25.3

(21.1)36.1

(12.9)33.8

(11.1) 25.1

(13.6)22.7

(18.2)2.3 15.2 15.6 23.4 36.5 33.8 27.6 19.8

1.0,47.7 4.1,55.7 7.2,42.2 10.5,42.7 5.6,89.6 26.0,41.6 4.2,36.8 1.0,89.6

N 10 9 8 6 13 2 5 53

(SD) 11.3

(16.3)10.3(9.2)

7.5(4.0)

8.8(4.5)

11.2 (7.1)

9.5(2.1)

5.6(2.9)

9.6(8.9)

6.0 8.0 7.5 8.0 11.0 9.5 6.0 8.0 4,57 2,32 4,16 4,16 2,28 8,11 1,8 1,57

a N 10 9 8 6 13 2 5 53

(SD) 91.9

(154.8)80.6

(81.9)55.1

(39.5)66.3

(40.9)94.6

(68.6)79.5

(29.0)39.2

(23.2)76.8

(83.9)39.0 56.0 53.0 56.5 86.0 79.5 43.0 56.0

22,526 8,272 22,141 22,135 8,233 59,100 1,58 1,526 b

N 10 9 8 6 13 2 5 53

(SD) 2.7

(3.68)2.4

(2.40)1.8

(1.04)2.2

(1.17)2.5

(1.85)2.0

(0.00)1.2

(0.84)2.2

(2.2)1.5 2.0 1.5 2.0 2.0 2.0 1.0 2.0

1,13 0,8 1,4 1,4 0,7 2,2 0,2 0,13 ab 4 4 13

53 22.7 mg 1.0 89.6 mg

9.6 1 57

76.8 1 526

2.2 0 13

2.00 mg/m2 0.13 1.80 mg/m2

7.5 11.3 2.00 mg/m2

5.6

2.7.6 DM98-194 19

58% 31/53 2 2 29

2 2.00 mg/m2 40%

2 1.45 mg/m2 1.60 mg/m2 1.80 mg/m2

65% 50% 56%

32% 17/53 2 2.7.6.2.1-11

2 1.60 mg/m2 54% 7/13

2 0.13 0.60 mg/m2 20% 2/10 0.75

0.90 mg/m2 33% 3/9 1.00 1.32 mg/m2 25% 2/8 1.45 mg/m2 33% 2/6

1.80 mg/m2 50% 1/2 2.00 mg/m2 0% 0/5

2.7.6.2.1-11 2

(mg/m2)PD

0.13-0.60 007 a 0.40 57 15 Yes No 008 0.40 12 3 Yes No

0.75-0.90 014 0.80 12 3 Yes No 015 0.80 32 8 No No 017 0.85 16 4 Yes No

1.00-1.32 021 1.00 9 3 Yes No 027 1.32 16 4 Yes No

1.45 029 1.45 16 4 Yes No 035 1.45 12 3 Yes No

1.60 037 1.60 12 3 Yes No 038 1.60 12 3 Yes No 040 1.60 11 3 No No 042 1.60 15 4 Yes No 044 1.60 28 7 Yes No 045 1.60 13 4 No b No 046 1.60 20 5 Yes No

1.80 049 1.80 11 3 Yes No a M34101-029b PD