Introduction
Materials and methods
Patients and inclusion criteria
Study design
Pharmacokinetics
Safety
Exploratory evaluation of efficacy
Results
Patients
Total | |
---|---|
Patients (N) | 21 |
Sex, N (%) | |
Male | 14 (66.7) |
Female | 7 (33.3) |
Age (years) | |
< 65, N (%) | 11 (52.4) |
≥ 65, N (%) | 10 (47.6) |
Mean ± SD | 62.5 ± 10.6 |
Median | 63.0 |
Range, 52–74 | 43–80 |
ECOG performance status, N (%) | |
0 | 16 (76.2) |
1 | 5 (23.8) |
2 | 0 (0.0) |
Tumor type, N (%) | |
Lung | 0 (0.0) |
Pancreas | 5 (23.8) |
Colorectal | 7 (33.3) |
Stomach | 0 (0.0) |
Esophagus | 1 (4.8) |
Biliary tract | 4 (19.0) |
Liver | 0 (0.0) |
Others | 4 (19.0) |
Stage of cancer, N (%) | |
IV | 9 (42.9) |
IVB | 2 (9.5) |
Refractory | 10 (47.6) |
Histopathological classification, N (%) | |
Small round cell tumor | 1 (4.8) |
Invasive ductal carcinoma | 1 (4.8) |
Adenocarcinoma | 15 (71.4) |
Clear cell carcinoma | 1 (4.8) |
Squamous cell carcinoma | 1 (4.8) |
Acral lentiginous melanoma | 1 (4.8) |
Unknown | 1 (4.8) |
TNM staging (T) at study onset, N (%) | |
T0 | 15 (71.4) |
T3 | 3 (14.3) |
T4 | 3 (14.3) |
TNM staging (N) at study onset, N (%) | |
N0 | 11 (52.4) |
N1 | 6 (28.6) |
N2 | 1 (4.8) |
N2b | 2 (9.5) |
N3 | 1 (4.8) |
TNM staging (M) at study onset, N (%) | |
M0 | 1 (4.8) |
M1 | 15 (71.4) |
M1b | 4 (19.0) |
M1c | 1 (4.8) |
Treatment history: surgerya, N (%) | |
0 | 5 (23.8) |
≥ 1 | 16 (76.2) |
Complete resectiona | 10 (47.6) |
Residual tumor presenta | 7 (33.3) |
Unknowna | 3 (14.3) |
Treatment history: radiotherapy, N (%) | |
0 | 18 (85.7) |
≥ 1 | 3 (14.3) |
Prior systemic regimens, N (%) | |
0 | 0 (0.0) |
1 | 3 (14.3) |
2 | 6 (28.6) |
3 | 3 (14.3) |
4 | 3 (14.3) |
5 | 2 (9.5) |
6 | 4 (19.0) |
KRAS mutations determined, N (%) | 4 (19.0) |
Pharmacokinetics
100 mg | 200 mg | 400 mg | 600 mg | 800 mg | 1000 mg | |
---|---|---|---|---|---|---|
Pharmacokinetic parameters on day 1 | ||||||
Patients (N) | 3 | 3 | 3 | 3 | 6 | 3 |
Cmax (ng/mL), mean ± SD | 1340 ± 473 | 2830 ± 822 | 3630 ± 876 | 4500 ± 1580 | 4790 ± 1100 | 4990 ± 1210 |
tmax (h) | ||||||
Median | 1.97 | 3.98 | 4.00 | 3.98 | 3.99 | 3.97 |
Range | 1.52–3.88 | 2.13–4.00 | 4.00–4.03 | 1.42–4.00 | 2.02–5.93 | 3.97–6.37 |
AUCinf (ng h/mL), mean ± SD | 4970 ± 1600 | 11,400 ± 3580 | 20,300 ± 3710 | 18,500 ± 3060 | 26,600 ± 4200 | 26,900a |
AUC12h (ng h/mL), mean ± SD | 4700 ± 1490 | 10,400 ± 3180 | 18,000 ± 4060 | 16,900 ± 2880 | 23,800 ± 3010 | 22,400 ± 2890 |
t1/2 (h), mean ± SD | 3.81 ± 0.25 | 4.16 ± 1.13 | 4.00 ± 1.88 | 3.50 ± 0.39 | 3.67 ± 0.81 | 9.11 ± 9.79 |
CL/F (L/h), mean ± SD | 21.6 ± 6.80 | 19.1 ± 7.35 | 20.1 ± 3.83 | 33.0 ± 5.25 | 30.7 ± 4.55 | 38.3a |
Pharmacokinetic parameters on day 21 | ||||||
Patients (N) | 2 | 3 | 3 | 3 | 6 | 3 |
Cmax (ng/mL), mean ± SD | 1180a1 | 2610 ± 837 | 3250 ± 1440 | 4870 ± 2390 | 3840 ± 2090 | 2630 ± 1450 |
tmax (h) | ||||||
Median | 4.05 | 3.93 | 3.97 | 2.10 | 2.98 | 3.95 |
Range | 4.05–4.05 | 3.92–4.00 | 3.97–6.00 | 2.00–4.00 | 1.42–5.98 | 2.00–3.97 |
AUC12h (ng h/mL), mean ± SD | 4610a | 10,500 ± 4450 | 14,800 ± 3520 | 18,700 ± 4710 | 16,300 ± 6240 | 15,700 ± 9100 |
Safety
100 mg | 200 mg | 400 mg | 600 mg | 800 mg | 1000 mg | Total | |
---|---|---|---|---|---|---|---|
Patients (N) | 3 | 3 | 3 | 3 | 6 | 3 | 21 |
All AEs, N (%) | 3 (100) | 3 (100) | 3 (100) | 3 (100) | 6 (100) | 3 (100) | 21 (100) |
Patients with AEs of grade ≥ 3, N (%) | 2 (66.7) | 1 (33.3) | 2 (66.7) | 0 (0.0) | 2 (33.3) | 2 (66.7) | 9 (42.9) |
Serious AEs, N (%) | 1 (33.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (4.8) |
Discontinuation because of AEs, N (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
All drug-related AEs, N (%) | 2 (66.7) | 3 (100) | 3 (100) | 3 (100) | 6 (100) | 2 (66.7) | 19 (90.5) |
Patients with drug-related AEs of grade ≥ 3, N (%) | 0 (0.0) | 0 (0.0) | 1 (33.3) | 0 (0.0) | 1 (16.7) | 2 (66.7) | 4 (19.0) |
Serious drug-related AEs, N (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Discontinuation because of drug-related AEs, N (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Dose-limiting toxicity (DLT), N (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Death, N (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
AEs observed in ≥ 3 patients, N (%) | |||||||
Diarrhea | 2 (66.7) | 2 (66.7) | 3 (100) | 3 (100) | 6 (100) | 2 (66.7) | 18 (85.7) |
Abdominal pain | 1 (33.3) | 0 (0.0) | 3 (100) | 0 (0.0) | 1 (16.7) | 1 (33.3) | 6 (28.6) |
Nausea | 1 (33.3) | 0 (0.0) | 2 (66.7) | 2 (66.7) | 1 (16.7) | 0 (0.0) | 6 (28.6) |
Decreased appetite | 1 (33.3) | 0 (0.0) | 1 (33.3) | 1 (33.3) | 4 (66.7) | 2 (66.7) | 9 (42.9) |
Vomiting | 0 (0.0) | 0 (0.0) | 1 (33.3) | 2 (66.7) | 1 (16.7) | 0 (0.0) | 4 (19.0) |
AEs observed at grade ≥ 3, N (%) | |||||||
Diarrhea | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (16.7) | 1 (33.3) | 2 (9.5) |
Anemia | 1 (33.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (33.3) | 2 (9.5) |
Ascites | 1 (33.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (4.8) |
Cholestatic jaundice | 0 (0.0) | 1 (33.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (4.8) |
Amylase increased | 0 (0.0) | 0 (0.0) | 1 (33.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (4.8) |
Hyponatremia | 1 (33.3)a | 0 (0.0) | 1 (33.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (9.5) |
Hypercalcemia | 0 (0.0) | 0 (0.0) | 1 (33.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (4.8) |
Hypophosphatemia | 0 (0.0) | 0 (0.0) | 1 (33.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (4.8) |
Bilirubin increased | 0 (0.0) | 1 (33.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (4.8) |
γ-GTP increased | 1 (33.3) | 1 (33.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (33.3) | 3 (14.3) |
AST increased | 0 (0.0) | 1 (33.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (4.8) |
ALP increased | 0 (0.0) | 1 (33.3) | 0 (0.0) | 0 (0.0) | 1 (16.7) | 1 (33.3) | 3 (14.3) |
Troponin T increased | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (33.3) | 1 (4.8) |
Hemoglobin decreased | 1 (33.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (33.3) | 2 (9.5) |
Lymphopenia | 1 (33.3)a | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (4.8) |
Decreased appetite | 1 (33.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (4.8) |
Cancer pain | 1 (33.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (4.8) |
Exploratory evaluation of efficacy
100 mg | 200 mg | 400 mg | 600 mg | 800 mg | 1000 mg | Total | |
---|---|---|---|---|---|---|---|
Patients (N) | 3 | 3 | 3 | 3 | 6 | 3 | 21 |
Response ratea, N (%) | |||||||
Complete response (CR) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Partial response (PR) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Stable disease (SD) | 1 (33.3) | 3 (100.0) | 2 (66.7) | 2 (66.7) | 1 (16.7) | 1 (33.3) | 10 (47.6) |
Progressive disease (PD) | 2 (66.7) | 0 (0.0) | 1 (33.3) | 1 (33.3) | 3 (50.0) | 2 (66.7) | 9 (42.9) |
Objective response rate (ORR): CR + PR | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Disease control rate (DCR): CR + PR + SD | 1 (33.3) | 3 (100.0) | 2 (66.7) | 2 (66.7) | 1 (16.7) | 1 (33.3) | 10 (47.6) |
Number of cycles completedb | |||||||
Median | 1 | 7 | 2 | 5 | 1 | 1 | 2 |
Range | 1–2 | 2–13 | 1–3 | 3–11 | 1–11 | 1–3 | 1–13 |
Progression-free survivalc (days) | |||||||
Median | 22 | 213 | 56 | 135 | 29 | 22 | 53 |
Range | 16–53 | 57–373 | 22–91 | 79–319 | 22–307 | 22–91 | 16–373 |