Carcinoma, Hepatocellular
Conditions
Keywords
Cancer, Liver Cancer, Hepatocellular carcinoma, HCC
Brief summary
The purpose of this study is to evaluate the safety and efficacy of doxorubicin plus sorafenib versus doxorubicin plus placebo in patients with advanced hepatocellular carcinoma (HCC).
Detailed description
In addition to the key secondary outcome parameters the following parameters will be assessed in an exploratory manner: relative time to progression (TTP), time to symptomatic progression (TTSP), response rate (RR) and overall survival between the 2 study populations. The possible and potential predictive assays of clinical benefit through an assessment of the correlation between the defined baseline characteristics and key clinical endpoints. The safety and tolerability will be assessed in the adverse event section. Doxorubicin pharmacokinetics in HCC patients treated with sorafenib versus placebo will be compared and the pharmacokinetic data will be correlated with doxorubicin-related adverse events (i.e., cardiotoxicity).
Interventions
DRUGSorafenib (Nexavar, BAY43-9006) plus Doxorubicin
Multi kinase inhibitor plus Chemotherapy
DRUGDoxorubicin/Placebo
Chemotherapy plus Placebo
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients who have a life expectancy of at least 12 weeks * Patients with advanced HCC (unresectable, and/or metastatic) which has been histologically or cytologically documented * Patients must have at least one tumor lesion that meets both of the following criteria: * can be accurately measured in at least one dimension according to Response Evaluation Criteria in Solid Tumors (RECIST) * has not been previously treated with local therapy * Patients who have received local therapy except chemoembolization, such as surgery, radiation therapy, hepatic arterial embolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation are eligible, provided that they either have a target lesion which has not been subjected to local therapy and/or the target lesion(s) within the field of the local therapy has shown an increase of 25% in the size. Local therapy must be completed at least 4 weeks prior to the baseline scan * Patients who have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
Exclusion criteria
* Previous or concurrent cancer that is distinct in primary site or histology from HCC, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, and superficial bladder tumors (Ta, Tis & T1). Any cancer curatively treated \> 3 years prior to entry is permitted * History of cardiac disease * Serious myocardial dysfunction * Active, clinically serious infections * Known history of Human Immunodeficiency Virus (HIV) infection * Known Central Nervous System (CNS) tumors including metastatic brain disease * Patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression (TTP) | from date of randomization of the first patient until 3 years later | TTP was defined as the time from randomization to radiological disease progression by independent assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | from date of randomization of the first patient until 3 years later | Time from the date of randomization to the date of the first documented radiological progression (as defined per independent central radiological assessment) or death, whichever occurs first |
| Time to Symptomatic Progression (TTSP) | from date of randomization of the first patient until 3 years later | Time from date of randomization to date of first documented symptomatic progression defined by Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index-8 (FHSI-8) assessment |
| Percentage of Participants in Each Category of Best Tumor Response | achieved during treatment or within 30 days after termination of active therapy | Percentage of participants with complete or partial response (CR or PR) confirmed according to Response Evaluation Criteria in Solid Tumors (RECIST) and achieved during treatment or 30 days after end of treatment. CR: disappearance of all clinical and radiological tumor lesions. PR: at least 30% decrease in sum of the longest diameters of tumor lesions. Stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease. |
| Overall Survival | from date of randomization of the first patient until 3 years later | The time from date of randomization to date of death |
| Time to Response (TTR) | from date of randomization until 3 years later at end of study | Time from date of randomization to date of first objective response (complete response \[CR\] or partial response \[PR\]) is documented and confirmed according to RECIST criteria |
| Percentage of Participants for Whom Disease Control Was Achieved | from date of randomization to end of treatment plus 30 days | Participants with disease control: those who have as best response complete response (CR), partial response (PR) or stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease) according to Response Evaluation Criteria in Solid Tumors (RECIST) |
| Duration of Response | from date of randomization of the first patient until 3 years later | Time from date of first objective response (complete response \[CR\] or partial response \[PR\]) to date progression is first documented (as defined per independent central radiological assessment) or death, whichever occurs first |
Countries
Argentina, Canada, Hong Kong, Russia, United Kingdom, United States
Participant flow
Recruitment details
Enrollment started on 13 Apr 2005 and the last study contact occurred on 11 Apr 2008. The study was conducted at 25 active centers in 6 countries (Argentina, Canada, Hong Kong, Russia, United Kingdom, and United States.)
Pre-assignment details
140 patients were screened, with 44 screen failures. The intent-to-treat (ITT) population (primary efficacy analysis) includes all randomized patients (96). The Safety population includes all patients who received at least 1 dose of study drug (95). The study consists of 2 periods: treatment period (not fixed but ended by any event) and follow-up.
Participants by arm
| Arm | Count |
|---|---|
| Sorafenib + Doxorubicin Sorafenib + Doxorubicin -- combination therapy: Sorafenib (Nexavar, BAY43-9006) 200 mg tablets by mouth (orally) twice daily + doxorubicin 60 mg/m2 intravenous infusion every 21 days for 6 cycles (18 weeks) | 47 |
| Placebo + Doxorubicin Placebo + Doxorubicin -- monotherapy: Sorafenib (Nexavar, BAY43-9006) matching placebo tablets by mouth (orally) twice daily + doxorubicin 60 mg/m2 intravenous infusion every 21 days for 6 cycles (18 weeks) | 49 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up | Death | 18 | 26 |
| Follow-up | Lost to Follow-up | 1 | 1 |
| Follow-up | Study terminated by sponsor | 10 | 6 |
Baseline characteristics
| Characteristic | Sorafenib + Doxorubicin | Total | Placebo + Doxorubicin |
|---|---|---|---|
| Age, Continuous Median (Full Range) | 66 years | 65 years | 65 years |
| Child Pugh Status 5 (Child-Pugh A) | 30 participants | 58 participants | 28 participants |
| Child Pugh Status 6 (Child-Pugh A) | 17 participants | 36 participants | 19 participants |
| Child Pugh Status >7 | 0 participants | 0 participants | 0 participants |
| Child Pugh Status 7 (Child-Pugh B) | 0 participants | 2 participants | 2 participants |
| Eastern Cooperative Group performance status (ECOG PS) at study entry Grade 0 | 22 participants | 38 participants | 16 participants |
| Eastern Cooperative Group performance status (ECOG PS) at study entry Grade 1 | 18 participants | 43 participants | 25 participants |
| Eastern Cooperative Group performance status (ECOG PS) at study entry Grade 2 | 4 participants | 7 participants | 3 participants |
| Eastern Cooperative Group performance status (ECOG PS) at study entry Grade 3 | 0 participants | 1 participants | 1 participants |
| Eastern Cooperative Group performance status (ECOG PS) at study entry missing | 3 participants | 7 participants | 4 participants |
| Sex: Female, Male Female | 16 Participants | 23 Participants | 7 Participants |
| Sex: Female, Male Male | 31 Participants | 73 Participants | 42 Participants |
| Tumor burden: Extrahepatic spread no | 23 participants | 40 participants | 17 participants |
| Tumor burden: Extrahepatic spread yes | 24 participants | 56 participants | 32 participants |
| Tumor burden: Macroscopic vascular invasion missing | 1 participants | 2 participants | 1 participants |
| Tumor burden: Macroscopic vascular invasion no | 33 participants | 65 participants | 32 participants |
| Tumor burden: Macroscopic vascular invasion yes | 13 participants | 29 participants | 16 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 47 / 47 | 48 / 48 |
| serious Total, serious adverse events | 19 / 47 | 20 / 48 |
Outcome results
Primary
Time to Progression (TTP)
TTP was defined as the time from randomization to radiological disease progression by independent assessment.
Time frame: from date of randomization of the first patient until 3 years later
Population: The intent-to-treat (ITT) population, primary population for efficacy analysis, includes all randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib + Doxorubicin | Time to Progression (TTP) | 263 days |
| Placebo + Doxorubicin | Time to Progression (TTP) | 147 days |
Comparison: The comparison between the 2 groups is done using the log rank test stratified by tumor burden. The null hypothesis is: TTP is the same in both treatment groups.p-value: 0.01695% CI: [0.33, 0.95]Log Rank
Secondary
Duration of Response
Time from date of first objective response (complete response \[CR\] or partial response \[PR\]) to date progression is first documented (as defined per independent central radiological assessment) or death, whichever occurs first
Time frame: from date of randomization of the first patient until 3 years later
Population: The ITT population, primary population for efficacy analysis, includes all randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib + Doxorubicin | Duration of Response | 199 days |
| Placebo + Doxorubicin | Duration of Response | 68 days |
Secondary
Overall Survival
The time from date of randomization to date of death
Time frame: from date of randomization of the first patient until 3 years later
Population: The ITT population, primary population for efficacy analysis, includes all randomized patients. The table below gives the lower and upper limit of the confidence interval; 999999999 = not estimable.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib + Doxorubicin | Overall Survival | 418 days |
| Placebo + Doxorubicin | Overall Survival | 199 days |
Comparison: The comparison between the 2 groups is done using the log rank test stratified by tumor burden. The null hypothesis is: TTP is the same in both treatment groupsp-value: 0.00795% CI: [0.37, 0.74]Log Rank
Secondary
Percentage of Participants for Whom Disease Control Was Achieved
Participants with disease control: those who have as best response complete response (CR), partial response (PR) or stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease) according to Response Evaluation Criteria in Solid Tumors (RECIST)
Time frame: from date of randomization to end of treatment plus 30 days
Population: The ITT population, primary population for efficacy analysis, includes all randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib + Doxorubicin | Percentage of Participants for Whom Disease Control Was Achieved | 63.8 Percentage of participants |
| Placebo + Doxorubicin | Percentage of Participants for Whom Disease Control Was Achieved | 30.6 Percentage of participants |
Secondary
Percentage of Participants in Each Category of Best Tumor Response
Percentage of participants with complete or partial response (CR or PR) confirmed according to Response Evaluation Criteria in Solid Tumors (RECIST) and achieved during treatment or 30 days after end of treatment. CR: disappearance of all clinical and radiological tumor lesions. PR: at least 30% decrease in sum of the longest diameters of tumor lesions. Stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease.
Time frame: achieved during treatment or within 30 days after termination of active therapy
Population: The ITT population, primary population for efficacy analysis, includes all randomized patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sorafenib + Doxorubicin | Percentage of Participants in Each Category of Best Tumor Response | Complete Response (CR) | 0.0 Percentage of participants |
| Sorafenib + Doxorubicin | Percentage of Participants in Each Category of Best Tumor Response | Partial Response (PR) | 4.3 Percentage of participants |
| Sorafenib + Doxorubicin | Percentage of Participants in Each Category of Best Tumor Response | Stable Disease (SD) | 66.0 Percentage of participants |
| Placebo + Doxorubicin | Percentage of Participants in Each Category of Best Tumor Response | Complete Response (CR) | 2.0 Percentage of participants |
| Placebo + Doxorubicin | Percentage of Participants in Each Category of Best Tumor Response | Partial Response (PR) | 0.0 Percentage of participants |
| Placebo + Doxorubicin | Percentage of Participants in Each Category of Best Tumor Response | Stable Disease (SD) | 49.0 Percentage of participants |
Secondary
Progression Free Survival (PFS)
Time from the date of randomization to the date of the first documented radiological progression (as defined per independent central radiological assessment) or death, whichever occurs first
Time frame: from date of randomization of the first patient until 3 years later
Population: The ITT population, primary population for efficacy analysis, includes all randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib + Doxorubicin | Progression Free Survival (PFS) | 242 days |
| Placebo + Doxorubicin | Progression Free Survival (PFS) | 85 days |
Comparison: The comparison between the 2 groups is done using the log rank test stratified by tumor burden. The null hypothesis is: TTP is the same in both treatment groupsp-value: 0.01895% CI: [0.45, 0.83]Log Rank
Secondary
Time to Response (TTR)
Time from date of randomization to date of first objective response (complete response \[CR\] or partial response \[PR\]) is documented and confirmed according to RECIST criteria
Time frame: from date of randomization until 3 years later at end of study
Population: The ITT population, primary population for efficacy analysis, includes all randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib + Doxorubicin | Time to Response (TTR) | 134 days |
| Placebo + Doxorubicin | Time to Response (TTR) | 40 days |
Secondary
Time to Symptomatic Progression (TTSP)
Time from date of randomization to date of first documented symptomatic progression defined by Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index-8 (FHSI-8) assessment
Time frame: from date of randomization of the first patient until 3 years later
Population: The ITT population, primary population for efficacy analysis, includes all randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib + Doxorubicin | Time to Symptomatic Progression (TTSP) | 208 days |
| Placebo + Doxorubicin | Time to Symptomatic Progression (TTSP) | 152 days |
Comparison: The comparison between the 2 groups is done using the log rank test stratified by tumor burden. The null hypothesis is: TTP is the same in both treatment groupsp-value: 0.03895% CI: [0.4, 1.05]Log Rank