Table 1. Summary of pharmacodynamic measurements and dose modifications.
| |
Run-in period |
Initial dose and dose modifications |
||||||
|---|---|---|---|---|---|---|---|---|
| Patient | pShift d0 | pShift d7 | pShift change (%)a | BP change (mm Hg)b | Sorafenib total daily dose on C1 d1c (mg) | Cycle(s) in which dose was modified | Final total daily dosed (mg) | Reason(s) for dose modification |
| 1 |
27.46 |
13.50 |
−50.8 |
4.7 |
4001 |
— |
400 |
|
| 2 |
11.96 |
−0.36 |
−103 |
13.3 |
800 |
— |
800 |
|
| 3 | 26.46 | 33.80 | 27.7 | −7 | 1200 | 2 | 800 | G2 Hand-foot syndrome (HFS) (intolerable) |
| |
|
|
|
|
|
2 |
400 |
Mucositis, diarrhoea, gas (all intolerable G2) |
| 4 | 40.23 | 37.83 | −5.97 | 9.3 | 1600 | 3 | 1200 | G3 HFS |
| |
|
|
|
|
|
3 |
800 |
G3 HFS |
| 5 |
17.80 |
9.63 |
−45.9 |
−3 |
800 |
8 |
400 |
G2 Fatigue |
| 6 |
32.80 |
44.06 |
34.4 |
−0.7 |
8002 |
13 |
400 |
G2 Diarrhoea (intolerable) |
| 7 |
46.66 |
53.46 |
14.7 |
1 |
4003 |
2 |
200* |
G2 HFS (intolerable) |
| 8 |
47.66 |
28.13 |
−40.9 |
11.7 |
1200 |
— |
1200 |
|
| 9 |
36.96 |
33.93 |
−8.2 |
21.7 |
4004 |
— |
400 |
|
| 10 |
51.66 |
33.37 |
−35.4 |
−2.3 |
800 |
1 |
400 |
G2 Nausea, vomiting and leg pain |
| 11 |
53.73 |
38.00 |
−29.3 |
9 |
8005 |
— |
800 |
|
| 12 |
12.20 |
2.23 |
−81.7 |
5.3 |
800 |
— |
800 |
|
| 13 |
11.23 |
19.95 |
77.6 |
12.3 |
4006 |
4 |
200* |
G2 Proteinuriae |
| 14 |
60.13 |
18.67 |
−12.1 |
−2 |
800 |
— |
800 |
|
| 15 |
48.33 |
27.40 |
−43.3 |
15.7 |
8007 |
— |
800 |
|
| 16 |
60.13 |
29.75 |
−50.5 |
−83.7 |
800 |
— |
800 |
|
| 17 |
51.00 |
11.57 |
−77.3 |
5 |
— |
— |
— |
|
| 18 |
47.73 |
58.53 |
22.6 |
−1 |
800 |
— |
800 |
|
| 19 |
29.06 |
10.30 |
−64.6 |
23 |
— |
— |
— |
|
| 20 |
58.03 |
62.93 |
8.4 |
16.3 |
8008 |
3 |
400 |
G2 Diarrhoea (intolerable) |
| 21 |
57.56 |
25.1 |
−56.4 |
−75 |
800 |
— |
800 |
|
| 22 | 48.00 | 43.68 | −9 | 8.7 | — | — | — | |
Abbreviations: BP=blood pressure; pShift=phosphoshift assay.
pShift changes from day 7 vs day 0 of the run-in period; results are expressed in percentage of increase or decrease of the baseline pShift value.
Average blood pressure on day 7 of run-in phase minus average blood pressure on day 0 of run-in phase (in mm Hg, calculated as follows: average blood pressure=(systolic blood pressure+2 × diastolic blood pressure)/3).
Cycle 1 day 1 dose, all cases b.i.d. During the run-in period, doses were modified due to the following reasons: 1: G3 vomiting; G2 rash (intolerable); 2: G3 HFS; 3: G2 HFS (intolerable); 4: G2 diarrhoea (intolerable); 5: G3 AST and ALT elevation; 6: G3 HFS; 7: G2 mucositis and fatigue (intolerable); 8: G3 AST and ALT elevation.
In two daily takes except in * (one daily take).
Proteinuria was 3.0 g per 24 h, but was sustained over several cycles and dose was reduced by investigator's decision.