Phase II Randomized Trial on Dose

Phase II Randomized Trial on Dose-Escalated
Sorafenib vs Best Supportive Care (BSC) in Patients
With Advanced Hepatocellular Carcinoma (HCC) With
Disease Progression on Prior Sorafenib Treatment
Pressiani T1, Rimassa L1, Boni C2, Labianca R3, Fagiuoli S3,
Ardizzoni A4, Foa P5, Cortesi E6, Porta C7, Artioli F8, Latini L9,
Carnaghi C1, Lutman FR1, Torzilli T1, Tommasini MA1, Cerianl R1,
Covini G1, Giordano L1, Locopo N1, Santoro A1.
1Humanitas
Cancer Center, Istituto Clinico Humanitas, Rozzano (MI), Italy; 2Arcispedale Santa
Maria Nuova, Reggio Emilia, Italy; 3Ospedali Riuniti, Bergamo, Italy; 4Azienda Ospedaliero Universitaria, Parma, Italy; 5Ospedale San Paolo - Polo Universitario, Milano, Italy;6Azienda
Policlinico Umberto I, Roma, Italy; 7I.R.C.C.S. Policlinico San Matteo, Pavia, Italy; 8Ospedale B.
Ramazzini, Carpi (MO), Italy; 9Ospedale Generale Provinciale, Macerata, Italy.
Study Design
Primary endpoint: PFS
Sorafenib
600 mg BID
49 patients
Advanced HCC
Child-Pugh Class A/B
Suitable for systemic
treatment
Sorafenib
400 mg BID
Randomization
1:1
PD
(101 patients)
(300 patients)
BSC
52 patients
From April 2007 to July 2008, 300 patients were prospectively treated with
sorafenib 400 mg BID. At documented radiological PD, 101 patients (34%)
were randomized: 49 patients (48.5%) to increased-dose sorafenib (600 mg
BID) + BSC and 52 patients (51.5%) to BSC, respectively
PD=radiological progression, PFS=progression-free survival.
Adapted from Pressiani T et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Baseline Patient Characteristics
Total
Sex
Male
Female
Child-Pugh Class
A
B
Histological subtype*
Trabecular
Mixed
Fibrolamellar
Missing
Extrahepatic spread*
Yes
No
Missing
Time at first relapse
≤4 months
>4 months
No. of Patients
(%)
101 (100)
Sorafenib
no. (%)
49 (48.5)
BSC
no. (%)
52 (51.5)
P value
.089
83 (82.2)
18 (17.8)
37 (75.5)
12 (24.5)
46 (88.5)
6 (11.5)
94 (93.1)
7 (6.9)
48 (98.0)
1 (2.0)
46 (88.5)
6 (11.5)
80 (79.2)
1 (1.0)
3 (3.0)
17 (16.8)
38 (97.4)
0 (0.0)
1 (2.6)
42 (93.33)
1 (2.22)
2 (4.44)
69 (68.31)
26 (25.74)
6 (5.94)
38 (82.6)
8 (17.4)
31 (63.3)
18 (36.7)
.113†
1.00†
.035
.269
49 (48.5)
52 (51.5)
21 (42.9)
28 (57.1)
28 (53.9)
24 (46.2)
Associations are tested using the Chi-square test.
*The sum does not add up to the total due to missing values.
†Associations are tested using the Fisher exact test.
Adapted from Pressiani T et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Progression-Free Survival
HR sorafanib vs BSC, 0.67; CI 95%: (0.43-1.06), Pvalue: .089
Risk reduction of 33%
PFS (months)
All Median (range)
3.58 (0.26-32.25)
Sorafenib Median (range)
3.91 (0.26-32.25)
CI=confidence interval, HR=hazard ratio.
Adapted from Pressiani T et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
BSC Median (range)
2.69 (0.49-19.51)
Time to Progression
HR sorafanib vs BSC, 0.59; CI 95%: (0.33-1.05), Pvalue: .070
Risk reduction of 41%
TTP (months)
All Median (range)
3.64 (0.62-32.25)
Sorafenib Median (range)
3.97 (0.62-32.2)
TTP=time to progression.
Adapted from Pressiani T et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
BSC Median (range)
2.0 (1.2-19.5)
Overall Survival (OS)
HR sorafanib vs BSC, 0.71; CI 95% : (0.47-1.08); Pvalue: .107
Risk reduction of 29%
TTP (months)
All Median (range)
6.11 (0.26-44.50)
Sorafenib Median (range)
7.55 (0.26-44.50)
Adapted from Pressiani T et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
BSC Median (range)
5.89 (0.49-26.64)
Adverse Events
Adverse Events (Grade 3/4)
Diarrhea
Hand foot skin reaction
Fatigue
Rash
Weight loss
Anemia
Stomatitis
Cachexia
Abdominal pain
Nausea and vomiting
Encephalopathy
Amylase increase
Thrombocytopenia
Pain (non abdominal)
Cardiovascular
Sorafenib
No. (%)
9 (12.2)
5 (6.3)
8 (16.3)
3 (6.1)
6 (12.2)
4 (8.1)
5 (6.3)
3 (4.1)
4 (8.1)
2 (3.8)
2 (3.8)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
BSC
No. (%)
6 (11.5)
8 (15.4)
4 (7.7)
4 (7.7)
1 (1.9)
1 (1.9)
0 (0.0)
2 (3.8)
0 (0.0)
1 (1.9)
0 (0.0)
1 (1.9)
1 (1.9)
1 (1.9)
1 (1.9)
Adapted from Pressiani T et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Pvalue
.335
.437
.226
1.000
.055
.196
.024
.672
.052
.610
.233
1.000
1.000
1.000
1.000
Drug Exposure
Adapted from Pressiani T et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
All Patients (300):
PFS and OS According to Child-Pugh Class
All (months)
n=234 Child-Pugh Class A (months)
n=62 Child-Pugh Class B (months)
Median (range)
OS
PFS
9.2 (0.4-46.7)
4.1 (0.4-35.3)
10.9 (0.5-46.7)
4.7 (0.5-35.3)
4.0 (0.4-27.3)
2.6 (0.4-27.3)
Adapted from Pressiani T et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Conclusions
These results demonstrate that increased-dose sorafenib in
HCC patients progressing on standard-dose sorafenib is
feasible, with an acceptable safety profile.
Trend toward improved PFS and OS, although not
statistically significant, may justify the use of increased
or standard dose of sorafenib beyond progression as an
active control arm in Phase II – III trials evaluating new
drugs as second-line therapy in HCC
Adapted from Pressiani T et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.