Introduction
Methods
Study design
Study participants
Inclusion criteria
Study objectives
Study assessments
Safety
Pharmacokinetics
Efficacy
Statistical methods
Results
Participants
Part 1: Solid tumor | Part 2: Gastric cancer | Part 2: HCC | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
Category | 2 mg/kg weekly (N = 3) | 4 mg/kg weekly (N = 3) | 8 mg/kg weekly (N = 3) | 12 mg/kg weekly (N = 6) | 4 mg/kg weekly (N = 5) | 8 mg/kg weekly (N = 5) | 12 mg/kg biweekly (N = 6) | 4 mg/kg weekly (N = 5) | 8 mg/kg weekly (N = 5) | 12 mg/kg biweekly (N = 5) |
Age (years), mean (SD) | 67.7 (4.9) | 52.0 (6.1) | 64.3 (9.0) | 58.8 (12.0) | 66.0 (7.7) | 67.0 (6.8) | 62.2 (14.0) | 66.2 (7.9) | 70.0 (9.0) | 55.6 (12.4) |
Sex, male | 2 | 1 | 1 | 3 | 5 | 5 | 4 | 4 | 3 | 4 |
Bodyweight (kg), mean (SD) | 55.9 (16.7) | 46.9 (1.9) | 60.8 (8.2) | 65. 5 (10.7) | 56.2 (7.3) | 54.6 (9.7) | 48. 3 (5.9) | 69.7 (18.9) | 56.0 (14.8) | 62.9 (9.7) |
ECOG PS | ||||||||||
0 | 3 | 2 | 1 | 5 | 1 | 3 | 3 | 3 | 4 | 4 |
1 | 0 | 1 | 2 | 1 | 4 | 2 | 3 | 2 | 1 | 1 |
Treatment history | ||||||||||
Previous surgery | 3 | 3 | 3 | 5 | 3 | 5 | 4 | 5 | 2 | 5 |
Previous radiotherapy | 1 | 1 | 0 | 2 | 0 | 1 | 0 | 0 | 0 | 3 |
Previous chemotherapy | 3 | 3 | 2 | 6 | 5 | 5 | 6 | 5 | 5 | 5 |
Primary malignancy | ||||||||||
Gastric cancer | 1 | 1 | 0 | 1 | ||||||
Breast cancer | 0 | 0 | 0 | 2 | ||||||
Gastrointestinal stromal tumor | 0 | 0 | 0 | 2 | ||||||
Adrenocortical cancer | 0 | 1 | 0 | 0 | ||||||
Extraskeletal chondrosarcoma | 0 | 0 | 1 | 0 | ||||||
Hypopharyngeal cancer | 0 | 1 | 0 | 0 | ||||||
Intrahepatic cholangiocarcinoma | 0 | 0 | 0 | 1 | ||||||
Lung cancer | 1 | 0 | 0 | 0 | ||||||
Malignant pheochromocytoma | 1 | 0 | 0 | 0 | ||||||
Renal pelvis cancer | 0 | 0 | 1 | 0 | ||||||
Thymic carcinoma | 0 | 0 | 1 | 0 | ||||||
Child–Pugh score | ||||||||||
5 | 3 | 3 | 4 | |||||||
6 | 2 | 2 | 1 | |||||||
Barcelona Clinic Liver Cancer stage | ||||||||||
Stage B | 1 | 1 | 0 | |||||||
Stage C | 4 | 4 | 5 |
Safety
Part 1: Solid tumor | Part 2: Gastric cancer | Part 2: HCC | Part 2 total (N = 31) | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
2 mg/kg weekly (N = 3) | 4 mg/kg weekly (N = 3) | 8 mg/kg weekly (N = 3) | 12 mg/kg weekly (N = 6) | Total (N = 15) | 4 mg/kg weekly (N = 5) | 8 mg/kg weekly (N = 5) | 12 mg/kg biweekly (N = 6) | Total (N = 16) | 4 mg/kg weekly (N = 5) | 8 mg/kg weekly (N = 5) | 12 mg/kg biweekly (N = 5) | Total (N = 15) | ||
Any TEAE | 2 | 2 | 2 | 2 | 8 | 3 | 3 | 2 | 8 | 4 | 3 | 3 | 10 | 18 |
Fatigue | 2 | 1 | 0 | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Constipation | 1 | 1 | 0 | 0 | 2 | 1 | 1 | 0 | 2 | 0 | 1 | 0 | 1 | 3 |
Decreased appetite | 0 | 1 | 1 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Hyperkalemia | 1 | 0 | 1 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Infusion-related reaction | 0 | 1 | 0 | 1 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Rash | 0 | 0 | 0 | 2 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Malaise | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 2 | 0 | 0 | 2 | 3 |
Hiccups | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 2 | 3 | 3 |
Bilirubin increased | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 1 | 1 | 0 | 2 | 3 |
Nausea | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 1 | 1 | 2 |
Vomiting | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 2 | 0 | 0 | 0 | 0 | 2 |
Pyrexia | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 2 | 0 | 0 | 0 | 0 | 2 |
Hypoalbuminemia | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 2 | 2 |
AST increased | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 2 | 2 |
ALT increased | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 2 | 2 |
Pharmacokinetics
PK parameter | Part 1: Solid tumor | Part 2: Gastric cancer | Part 2: HCC | |||||||
---|---|---|---|---|---|---|---|---|---|---|
2 mg/kg weekly (N = 3) | 4 mg/kg weekly (N = 3) | 8 mg/kg weekly (N = 3) | 12 mg/kg weekly (N = 6) | 4 mg/kg weekly (N = 5) | 8 mg/kg weekly (N = 5) | 12 mg/kg biweekly (N = 6) | 4 mg/kg weekly (N = 5) | 8 mg/kg weekly (N = 5) | 12 mg/kgbiweekly (N = 5) | |
Cycle 1, day 1 | ||||||||||
Cmax (μg/mL) | 41.6 ± 10.9 | 104 ± 19.3 | 182 ± 12.5 | 258 ± 41.1 | 67.8 ± 10.4 | 174 ± 39.5 | 243 ± 32.5 | 93.9 ± 14.6 | 181 ± 25.5 | 282 ± 41.7 |
tmax (h) | 1.200 (1.00–1.77) | 2.000 (1.07–4.95) | 2.380 (1.65–2.55) | 2.985 (1.83–4.00) | 1.120 (1.08–1.60) | 2.000 (1.48–2.03) | 1.850 (1.75–5.63) | 1.380 (1.03–5.13) | 2.100 (1.42–3.65) | 2.650 (1.75–6.30) |
AUC(0–24h) (μg•h/mL) | 802 ± 227 | 1850 ± 384 | 3420 ± 656 | 4740 ± 648 | 1280 ± 184 | 3020 ± 800 | 4380 ± 906 | 1730 ± 347 | 3210 ± 484 | 5200 ± 575 |
AUC(0–68h) (μg•h/mL) | 3000 ± 862 | 6680 ± 1080 | 14,300 ± 2520 | 20,200 ± 2700 | 4970 ± 675 | 13,800 ± 4040 | – | 6290 ± 1120 | 12,800 ± 2370 | – |
AUC(0–336h) (μg•h/mL) | – | – | – | – | – | – | 26,100 ± 4630 | – | – | 29,300 ± 1930 |
AUC(0–inf) (μg•h/mL) | 3580 ± 1150 | 8860 ± 1900a | 21,200 ± 4030a | 29,400 ± 3460a | 6450 ± 1170 | 22800d | 31,400 ± 6000e | 7760 ± 1380c | 20,400 ± 4300f | 36,300 ± 4160 |
t½ (h) | 62.6 ± 9.78 | 72.2 ± 14.7a | 140 ± 55.2 | 168 ± 70.7 | 77.9 ± 18.0 | 154 ± 43.3c | 156 ± 66.6 | 89.8 ± 50.0 | 107 ± 37.0 | 142 ± 30.7 |
CL (L/h) | 0.0324 ± 0.00931 | 0.0222 ± 0.00629a | 0.0220 ± 0.000424a | 0.0313 ± 0.0100a | 0.0355 ± 0.00519 | 0.0197 d | 0.0198 ± 0.00468 e | 0.0374 ± 0.00991 c | 0.0266 ± 0.00794 f | 0.0210 ± 0.00262 |
Vss (L) | 2.86 ± 0.407 | 2.20 ± 0.318a | 3.48 ± 0.467a | 4.45 ± 1.18a | 3.90 ± 0.582 | 3.27d | 3.55 ± 0.990e | 3.71 ± 1.31c | 3.88 ± 1.14f | 4.12 ± 0.826 |
MRT (h) | 90.8 ± 13.6 | 101 ± 14.3a | 158 ± 18.4a | 144 ± 7.78a | 112 ± 25.2 | 166d | 182 ± 35.2e | 98.2 ± 19.7c | 147 ± 21.0 | 196 ± 30.8 |
Cycle 1, day 22 /Cycle 2, day 1 | ||||||||||
Cmax (μg/mL) | 51.3 ± 14.8 | 152 ± 16.5 | 353 ± 36.6 | 417 ± 100 | 92.7 ± 19.9 | 264 ± 67.5 | 284 ± 48.1c | 125 ± 22.6 | 247 ± 49.2 | 374 ± 54.2 |
tmax (h) | 2.580 (1.50–4.58) | 1.520 (1.10–1.63) | 1.180 (1.00–5.12) | 2.975 (2.40–5.52) | 2.550 (1.05–2.73) | 1.300 (0.87–2.08) | 2.160 (1.95–3.25)c | 1.620 (1.15–4.72) | 1.550 (0.98–2.17) | 2.700 (1.77–3.60) |
AUC(0–168h) (μg•h/mL) | 4020 ± 1350 | 13,500 ± 1800 | 29,600 ± 5950 | 42,700 ± 9150b | 8710 ± 2210 | 24,900 ± 7090 | – | 10,200 ± 1960 | 20,100 ± 4050 | – |
AUC(0–336h) (μg•h/mL) | – | – | – | – | – | – | 39,700 ± 4840c | – | – | 42,700 ± 7270 |
t½ (h) | 85.3 ± 28.3 | 219 ± 138a | 121 ± 5.66a | 180 ± 85.2b | 142 ± 25.6c | 193 ± 144 | 179 ± 26.2c | 98.9 ± 25.9c | 119 ± 23.2 | 210 ± 113 c |
Efficacy
Category | Part 1: Solid tumor | Part 2: Gastric cancer | Part 2: HCC | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
2 mg/kg weekly (N = 3) | 4 mg/kg weekly (N = 3) | 8 mg/kg weekly (N = 3) | 12 mg/kg weekly (N = 6) | Total (N = 15) | 4 mg/kg weekly (N = 5) | 8 mg/kg weekly (N = 5) | 12 mg/kg biweekly (N = 6) | Total (N = 16) | 4 mg/kg weekly (N = 5) | 8 mg/kg weekly (N = 5) | 12 mg/kg biweekly (N = 5) | Total (N = 15) | |
Best overall response | |||||||||||||
Evaluable, n | 3 | 3 | 3 | 6 | 15 | 5 | 5 | 5 | 15 | 5 | 5 | 5 | 15 |
Complete response (CR), n | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Partial response (PR), n | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Stable disease (SD), n (%) | 2 (66.7) | 1 (33.3) | 2 (66.7) | 1 (16.7) | 6 (40.0) | 0 | 1 (20.0) | 1 (20.0) | 2 (13.3) | 4 (80.0) | 2 (40.0) | 2 (40.0) | 8 (53.3) |
Progressive disease (PD), n (%) | 1 (33.3) | 2 (66.7) | 1 (33.3) | 5 (83.3) | 9 (60.0) | 5 (100.0) | 4 (80.0) | 4 (80.0) | 13 (86.7) | 1 (20.0) | 3 (60.0) | 3 (60.0) | 7 (46.7) |
Not evaluable (NE), n | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Not determined, na | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 |
Objective response rate (CR + PR), nb | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Disease control rate (CR + PR + SD ≥ 7 weeks), n (%)b | 2 (66.7) | 1 (33.3) | 2 (66.7) | 1 (16.7) | 6 (40.0) | 0 | 1 (20.0) | 1 (20.0) | 2 (13.3) | 4 (80.0) | 2 (40.0) | 2 (40.0) | 8 (53.3) |