Phase I trial of combination chemotherapy with gemcitabine, cisplatin, and S-1 in patients with advanced biliary tract cancer

Table 1 Doses and treatment schedules for each level

	Gemcitabine	Cisplatin	S-1 (mg/d, Days 1-7, 15-21)
	(mg/m2, Days 1, 15)		BSA < 1.25	1.25 < BSA < 1.5	BSA > 1.5
Level -1	800	20	60	80	100
Level 0	800	25	60	80	100
Level 1	1000	25	60	80	100
Level 2	1000	25	80	100	120

BSA: Body surface area.

Table 2 Patient characteristics

Characteristic	n (%)
Sex
Male	10 (83)
Female	2 (17)
Median age	69 (range 44-77)
Primary lesion
Intrahepatic	2 (17)
Extrahepatic	3 (25)
Gallbladder	7 (58)
Ampulla of vater	0 (0)
Disease status
Unresectable	12 (100)
Recurrent	0 (0)
Performance status (0/1)	12/0
Biliary drainage	6 (50)
Median CEA (ng/mL)	3 (range 1.1-33.4)
Median CA19-9 (U/mL)	156.5 (range 1.0- > 10000)

CEA: Carcinoembryonic antigen; CA: Carbohydrate antigen.

Table 3 Dose-limiting toxicities at each level

Level	Age	Sex	Primary lesion	Biliary drainage	DLT	Response (RECIST)
0	71	M	Extrahepatic	Yes	None	PR
0	73	M	Extrahepatic	Yes	None	SD
0	63	F	Gallbladder	No	None	PD
1	77	M	Intrahepatic	Yes	Gr 4 febrile neutropenia and leucopenia, Gr 3 thrombocytopenia	PD
1	67	M	Gallbladder	Yes	None	NE
1	64	M	Gallbladder	No	None	SD
1	70	M	Extrahepatic	Yes	None	SD
1	72	M	Gallbladder	No	None	PR
1	74	M	Gallbladder	No	None	PR
2	58	M	Intrahepatic	No	None	PR
2	68	F	Gallbladder	No	None	SD
2	44	M	Gallbladder	Yes	None	PD

DLT: Dose-limiting toxicities; Gr: Grade; NE: Not evaluable; PD: Progressive disease; PR: Partial response; SD: Stable disease.

Table 4 Hematologic adverse events during the first cycle

	Level 0	(n = 3)	Level 1	(n = 6)	Level 2	(n = 3)
	Gr 1-2	Gr 3-4	Gr 1-2	Gr 3-4	Gr 1-2	Gr 3-4
Neutropenia	0	0	0	1	0	1
Leucopenia	1	0	2	1	1	0
Thrombocytopenia	2	0	1	1	0	0
Anemia	2	0	1	0	0	0
Febrile neutropenia	NA	0	NA	1	NA	0

NA: Not applicable.

Table 5 Non-hematologic adverse events during the first cycle

	Level 0	(n = 3)	Level 1	(n = 6)	Level 2	(n = 3)
	Gr 1-2	Gr 3-4	Gr 1-2	Gr 3-4	Gr 1-2	Gr 3-4
Anorexia	2	0	1	0	2	0
Nausea	1	0	1	0	0	0
Vomiting	1	0	0	0	0	0
Fatigue	0	0	0	0	2	0
Constipation	1	0	1	0	0	0
Fever	1	0	2	0	0	0
Biliary tract infection	NA	3	NA	0	NA	1
Infections (others)	0	0	0	2	0	0
AST	3	0	2	0	0	0
ALT	2	0	2	0	0	0
Hyperbilirubinemia	2	0	1	0	1	0
Creatinine	0	0	3	0	0	0

NA: Not applicable; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase.