Hepatocellular Carcinoma
Conditions
Keywords
Hepatocellular Carcinoma, HCC, Liver Cancer
Brief summary
Open-label study to evaluate the safety and tolerability of Sorafenib dose ramp-up (starting at a lower dose and then gradually increasing the dose) versus standard Sorafenib dosing in subjects with unresectable and/or metastatic hepatocellular carcinoma.
Detailed description
This is an open-label study that investigates the impact of a dose ramp-up strategy for sorafenib in patients with HCC. Clinical trial and post-marketing data suggest that sorafenib dose reductions and discontinuations due to adverse events are common and limit the drug's effectiveness. It is our hypothesis that a dose escalation strategy for sorafenib will improve the tolerability and allow a greater percentage of patients to remain on drug. The primary end-point of the study is the total accumulated and median daily dose of sorafenib delivered at month 2 and 4.
Interventions
DRUGSorafenib Standard Dosing Regimen
Sorafenib 400 mg twice daily until wk 24 or end of treatment
DRUGSorafenib Ramp-Up Regimen
200 mg daily, Day 0-Day 13 200 mg twice daily, Day 14-Day 20 600 mg daily, Day 21-Day 27 400 mg twice daily, Day 28 until end of treatment400 mg twice daily
Sponsors
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* HCC must be unresectable and/or metastatic * CPT score \<9 at the time of screening (that is all Child A and Child B with a score of 7 or 8) * Age 20-75 years * Signed informed consent * EGD for variceal screening performed as per standard of care prophylaxis with non-selective beta-blockers or ligation * ECOG Performance Status ≤ 2. * Adequate bone marrow, liver and renal function as assessed by the following: 1. Hemoglobin \> 8.5 g/dl 2. Absolute neutrophil count (ANC) \> 1,500/mm3 3. Platelet count \> 50,000/mm3 4. Total bilirubin \< 3 mg/dl 5. ALT and AST ( \< 5 x ULN) 6. Creatinine \< 1.5 times ULN * Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment * Women of childbearing potential and non-surgically sterile men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation. Men should use adequate birth control for at least three months after the last administration of sorafenib. * Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures. * INR\< 2.3. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable. * Life expectancy of at least 24 weeks
Exclusion criteria
* Absence of informed consent * Child-Pugh score \>9 * ECOG PS \>2 * Active alcohol dependence per PI discretion * History of organ or bone marrow transplant * Plans to relocate from the study center within the period of the trial * Pregnancy or breastfeeding * Contraindications to sorafenib 1. Cardiac disease: Congestive heart failure \> class II NYHA. Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months. 2. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy. 3. Known brain metastasis. Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis. 4. Uncontrolled hypertension defined as systolic blood pressure \> 150 mmHg or diastolic pressure \> 90 mmHg, despite optimal medical management. * Known human immunodeficiency virus (HIV) infection * Active clinically serious infection \> CTCAE Grade 2. * Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months. * Bleeding 1. Pulmonary hemorrhage/bleeding event \> CTCAE Grade 2 within 4 weeks of first dose of study drug. 2. Any other hemorrhage/bleeding event \> CTCAE Grade 3 within 4 weeks of first dose of study drug. 3. Evidence or history of bleeding diathesis or coagulopathy * Serious non-healing wound, ulcer, or bone fracture. * Major surgery, open biopsy or significant traumatic injury within 4 weeks prior to first study drug. * Use of St. John's Wort or rifampin (rifampicin). * Known or suspected allergy to sorafenib or any agent given in the course of this trial. * Any condition that impairs patient's ability to swallow whole pills. * Any malabsorption problem.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total (Cumulative) Dose Delivery of Sorafenib | 4 months-1/12/2010-1/27/14 | This outcome measure table shows the median cumulative dose delivered to the subjects randomized to the standard dosing regimen (N=63) and ramp-up regimen (N=57) at 4 months of treatment. |
| Cumulative Dose of Sorafenib | 11/22/2010-1/27/14 | Table below shows mean cumulative dose of sorafenib for each of the dosing regimens. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frequency and Severity of Adverse Events According to National Cancer Institute- CTCAE | 11/22/2010-3/10/2014 | The total number of CTCAE (Common Terminology Criteria) grade 5 adverse events was collected for each dosing regimen beginning at baseline through 6 months of treatment. |
| Safety and Efficacy of Sorafenib Dosing Regimens | Baseline-End of Treatment (11/22/2010-3/10/2014) | Safety of Sorafenib was assessed by the frequency and severity of adverse events according to NCI-CTCAE grading |
| Number of Subjects With Dose Reductions | 11/22/2010-3/10/2014 | — |
| Number of Subjects With Dose Interruptions | Baseline-End of Treatment (11/22/2010-3/10/2014) | — |
| Safety of Dosing Regimens as Assessed by the Frequency and Severity of Adverse Events According to National Cancer Institute- CTCAE | 11/22/2010-3/10/2014 | The total number of CTCAE (Common Terminology Criteria) grade 4 adverse events was collected for each dosing regimen beginning at baseline until Week 24/Early Termination Visit. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sorafenib Standard Dosing Regimen Sorafenib 400 mg (2 tablets of 200 mg) twice daily until end of treatment or week 24 | 63 |
| Sorafenib Ramp-Up Regimen 200 mg daily from Day 0-Day 13, 200 mg twice daily from Day 14-Day 20, 600 mg daily from Day 21-Day 27, 400 mg twice daily beginning Day 28 until end of treatment or Week 24 | 57 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 15 |
| Overall Study | Death | 12 | 10 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 2 |
Baseline characteristics
| Characteristic | Sorafenib Ramp-Up Regimen | Sorafenib Standard Dosing Regimen | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 00 Participants | 00 Participants | 0 Participants |
| Age, Categorical >=65 years | 27 Participants | 24 Participants | 51 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants | 39 Participants | 69 Participants |
| Age, Continuous | 63.5 years STANDARD_DEVIATION 7.5 | 62.0 years STANDARD_DEVIATION 6.8 | 62.7 years STANDARD_DEVIATION 7.2 |
| Region of Enrollment United States | 57 participants | 63 participants | 120 participants |
| Sex: Female, Male Female | 10 Participants | 12 Participants | 22 Participants |
| Sex: Female, Male Male | 47 Participants | 51 Participants | 98 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 62 / 63 | 57 / 57 |
| serious Total, serious adverse events | 16 / 63 | 13 / 57 |
Outcome results
Primary
Cumulative Dose of Sorafenib
Table below shows mean cumulative dose of sorafenib for each of the dosing regimens.
Time frame: 11/22/2010-1/27/14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sorafenib Standard Dosing Regimen | Cumulative Dose of Sorafenib | 53692 mg | Standard Deviation 33411 |
| Sorafenib Ramp-Up Regimen | Cumulative Dose of Sorafenib | 41523 mg | Standard Deviation 28783 |
Primary
Total (Cumulative) Dose Delivery of Sorafenib
This outcome measure table shows the median cumulative dose delivered to the subjects randomized to the standard dosing regimen (N=63) and ramp-up regimen (N=57) at 4 months of treatment.
Time frame: 4 months-1/12/2010-1/27/14
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib Standard Dosing Regimen | Total (Cumulative) Dose Delivery of Sorafenib | 49800 mg |
| Sorafenib Ramp-Up Regimen | Total (Cumulative) Dose Delivery of Sorafenib | 38000 mg |
p-value: 0.0262Wilcoxon rank sum test
Secondary
Frequency and Severity of Adverse Events According to National Cancer Institute- CTCAE
The total number of CTCAE (Common Terminology Criteria) grade 5 adverse events was collected for each dosing regimen beginning at baseline through 6 months of treatment.
Time frame: 11/22/2010-3/10/2014
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib Standard Dosing Regimen | Frequency and Severity of Adverse Events According to National Cancer Institute- CTCAE | 9 Grade 5 Adverse Events |
| Sorafenib Ramp-Up Regimen | Frequency and Severity of Adverse Events According to National Cancer Institute- CTCAE | 8 Grade 5 Adverse Events |
Secondary
Number of Subjects With Dose Interruptions
Time frame: Baseline-End of Treatment (11/22/2010-3/10/2014)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib Standard Dosing Regimen | Number of Subjects With Dose Interruptions | 29 participants |
| Sorafenib Ramp-Up Regimen | Number of Subjects With Dose Interruptions | 20 participants |
Secondary
Number of Subjects With Dose Reductions
Time frame: 11/22/2010-3/10/2014
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib Standard Dosing Regimen | Number of Subjects With Dose Reductions | 40 participants |
| Sorafenib Ramp-Up Regimen | Number of Subjects With Dose Reductions | 34 participants |
Secondary
Safety and Efficacy of Sorafenib Dosing Regimens
Safety of Sorafenib was assessed by the frequency and severity of adverse events according to NCI-CTCAE grading
Time frame: Baseline-End of Treatment (11/22/2010-3/10/2014)
Population: The total number of CTCAE (Common Terminology Criteria) grade 3 adverse events was collected for each dosing regimen
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib Standard Dosing Regimen | Safety and Efficacy of Sorafenib Dosing Regimens | 92 Grade 3 adverse events |
| Sorafenib Ramp-Up Regimen | Safety and Efficacy of Sorafenib Dosing Regimens | 101 Grade 3 adverse events |
Secondary
Safety of Dosing Regimens as Assessed by the Frequency and Severity of Adverse Events According to National Cancer Institute- CTCAE
The total number of CTCAE (Common Terminology Criteria) grade 4 adverse events was collected for each dosing regimen beginning at baseline until Week 24/Early Termination Visit.
Time frame: 11/22/2010-3/10/2014
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib Standard Dosing Regimen | Safety of Dosing Regimens as Assessed by the Frequency and Severity of Adverse Events According to National Cancer Institute- CTCAE | 19 Grade 4 adverse events |
| Sorafenib Ramp-Up Regimen | Safety of Dosing Regimens as Assessed by the Frequency and Severity of Adverse Events According to National Cancer Institute- CTCAE | 15 Grade 4 adverse events |