Liver Cancer
Conditions
Keywords
localized unresectable adult primary liver cancer, recurrent adult primary liver cancer, adult primary hepatocellular carcinoma
Brief summary
RATIONALE: Drugs used in chemotherapy, such as liposomal doxorubicin, cisplatin, and mitomycin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping the cells from dividing. Chemoembolization kills tumor cells by blocking the blood flow to the tumor and keeping chemotherapy drugs near the tumor. Monoclonal antibodies, such as bevacizumab, can kill any tumor cells that are left after chemoembolization by blocking their ability to grow and spread. PURPOSE: This randomized phase II trial is studying to see if chemoembolization followed by bevacizumab works better than chemoembolization alone in treating patients who have liver cancer that cannot be removed with surgery.
Detailed description
OBJECTIVES: * Compare neovessel formation at 8 and 14 weeks after hepatic arterial chemoembolization in patients with unresectable hepatocellular carcinoma treated with bevacizumab versus no bevacizumab (observation after chemoembolization only). * Compare time to progression, objective response rate, and tumor marker progression in patients treated with these regimens. * Determine the pharmacokinetics of bevacizumab in patients with liver function impairment. * Determine the toxic effects of this drug in these patients. * Compare the cancer biomarker pattern of peripheral blood cells and plasma before and after chemoembolization in patients treated with these regimens. OUTLINE: This is a randomized, open-label study. All patients receive hepatic artery chemotherapy (chemoembolization) comprising doxorubicin HCl liposome, cisplatin, and mitomycin on day 8 and possibly on day 92. Patients are then randomized to 1 of 2 treatment arms. * Arm I: Patients receive bevacizumab IV over 30-90 minutes once every 2 weeks beginning 1 week prior to the first chemoembolization. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. * Arm II: Patients do not receive bevacizumab. Patients in arm II may cross-over receive bevacizumab as in arm I if recurrent tumor is evident at week 14 by CT scan or MRI or a 50% or greater increase in AFP level has occurred since day 8 chemoembolization. PROJECTED ACCRUAL: A total of 30 patients (15 per treatment arm) will be accrued for this study.
Interventions
BIOLOGICALbevacizumab
Given IV, 10mg/kg evey two weeks starting 1 week prior to the first chemoembolization. Patients crossed over to the Bevacizumab arm will receive Bevacizumab after week 14 at the same dose.
Sponsors
National Cancer Institute (NCI)
Genentech, Inc.
Jonsson Comprehensive Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \> 18 year old * Histologically or cytologically documented HCC * Patients must have bi-dimensional measurable disease by CT or MRI scan that does not exceed 50% of the liver parenchyma * Patients must be considered clinical candidates for chemoembolization, with at least one lesion \> 3cm and no lesion \> 15cm in its longest diameter * Patients awaiting cadaveric orthotopic liver transplantation are eligible if they meet all other criteria. These patients must have a model for end-stage liver disease priority score \< 28 points at entry * Cirrhosis Child-Pugh class A or B * Patients with documented grad III varices or prior history of UGI bleeding will require endoscopic evaluation prior to treatment under this protocol. * Platelet count equal or greater than 60,000/μL * Female patients must use effective contraception, be surgically sterile or be postmenopausal; male patients must be using barrier contraception or be surgically sterile * Patients must be willing and able to comply with all study requirements and have signed the informed consent
Exclusion criteria
* Previous history of liver transplantation * Fibrolamellar histology * Prior antiangiogenesis therapy * Presence of extrahepatic disease * Presence of biliary obstruction defined as biliary dilatation and total bilirubin \> 2.5mg/dl * Thrombosis of the main portal vein * Absolute contraindications to doxorubicin, mitomycin-C, cisplatin, iodinated contrast material, Avitene or dexamethasone treatment * Other active malignancies during the past year (except for non-melanoma skin cancer or in situ carcinomas) * ECOG PS\> 2 or life expectancy \< 12 weeks * History or evidence upon physical examination of CNS disease * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, or anticipation of need for major surgical procedure within 3 months of study entry; fine needle aspirations within 7 days prior to Day 0 * Current or recent (within the 10 days prior to Day 0) use of full-dose oral or parenteral anticoagulants (except as required to maintain patency of preexisting, permanent indwelling IV catheters) or thrombolytic agent (for subjects receiving warfarin, international normalized ration of \< 1.5) * Chronic, daily treatment with aspirin (\> 325mg/day) or nonsteroidal anti-inflammatory medications * Positive pregnancy test or lactation * Proteinuria at baseline or clinically significant impairment of renal function. Subjects unexpectedly discovered to have \> 1+ proteinuria at baseline should undergo a 24-hour urine collection, which must be an adequate collection and must demonstrate \< 500 mg of protein/24 hr to allow participation in the study * Serious, nonhealing wound, ulcer, or bone fracture * Evidence of bleeding diathesis or coagulopathy * Current or recent (within the 28 days prior to Day 0) participation in another experimental drug study * Clinically significant cardiovascular disease, New York Heart Association Grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, or Grade II or greater peripheral vascular disease within 1 year prior to Day 0 * Prior history of hypertensive crisis of hypertensive encephalopathy * History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1 * History of hemoptysis within 1 month prior to Day 1 * Significant vascular disease within 6 months prior to Day 1 * Screening clinical laboratory values: * ANC of \< 1500/μL * INR of \> 1.5 * Total bilirubin of \> 2.5mg/dL * AST or ALT \> 5 times upper limit of normal * Serum creatinine of \> 2.0 mg/dL or creatinine clearance \< 45 mL/min * Hemoglobin of \< 8.5 gm/dL * History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the subject at high risk from treatment complications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neovessel Formation as Measured by Angiogram at 14 Weeks | 14 weeks | Angiograms were assessed for changes in vascularity. The numbers indicate how many subjects in each group showed neovessel formation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | 16 weeks | Progression free survival (PFS) at 16 weeks (end of the core phase). |
| Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | 16 weeks | — |
| Assess Pharmakokinetics of Bevacizumab in Liver Disease | day 85 | bevacizumab serum concentrations |
| Measure (Vascular Endothelial Growth Factor)VEGF Before and After TACE With and Without Bevacizumab | 21 days after TACE | — |
Countries
United States
Participant flow
Recruitment details
date of recruitment period August 2003- October 2008. Types of location: Academic medical clinics and community medical clinics.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (TACE-BEV Arm) Patients receive bevacizumab IV over 30-90 minutes once every 2 weeks beginning 1 week prior to the first (transarterial chemoembolization TACE)chemoembolization at a dose of 10 mg/kg. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.
bevacizumab : Given IV, 10mg/kg evey two weeks starting 1 week prior to the first chemoembolization.
Patients crossed over to the Bevacizumab arm will receive Bevacizumab after week 14 at the same dose. | 15 |
| Arm II (TACE-O Arm ) Observation | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | disease burden | 0 | 3 |
| Overall Study | refused angio | 0 | 3 |
Baseline characteristics
| Characteristic | Arm I (TACE-BEV Arm) | Arm II (TACE-O Arm ) | Total |
|---|---|---|---|
| Age, Customized Median age | 61 years | 58 years | 59.5 years |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 13 Participants | 12 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 15 | 14 / 14 |
| serious Total, serious adverse events | 5 / 15 | 1 / 14 |
Outcome results
Primary
Neovessel Formation as Measured by Angiogram at 14 Weeks
Angiograms were assessed for changes in vascularity. The numbers indicate how many subjects in each group showed neovessel formation.
Time frame: 14 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (TACE-BEV Arm) | Neovessel Formation as Measured by Angiogram at 14 Weeks | 2 participants |
| Arm II (TACE-O Arm ) | Neovessel Formation as Measured by Angiogram at 14 Weeks | 3 participants |
Secondary
Assess Pharmakokinetics of Bevacizumab in Liver Disease
bevacizumab serum concentrations
Time frame: day 85
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Arm I (TACE-BEV Arm) | Assess Pharmakokinetics of Bevacizumab in Liver Disease | Day 8 | 83.2 micrograms/mL |
| Arm I (TACE-BEV Arm) | Assess Pharmakokinetics of Bevacizumab in Liver Disease | Day 11 | 60.9 micrograms/mL |
| Arm I (TACE-BEV Arm) | Assess Pharmakokinetics of Bevacizumab in Liver Disease | Peak Day 1 | 203 micrograms/mL |
| Arm I (TACE-BEV Arm) | Assess Pharmakokinetics of Bevacizumab in Liver Disease | Peak Day 15 | 237 micrograms/mL |
| Arm I (TACE-BEV Arm) | Assess Pharmakokinetics of Bevacizumab in Liver Disease | Trough Day 15 | 35.4 micrograms/mL |
| Arm I (TACE-BEV Arm) | Assess Pharmakokinetics of Bevacizumab in Liver Disease | Peak Day 29 | 297 micrograms/mL |
| Arm I (TACE-BEV Arm) | Assess Pharmakokinetics of Bevacizumab in Liver Disease | Trough Day 29 | 74.3 micrograms/mL |
| Arm I (TACE-BEV Arm) | Assess Pharmakokinetics of Bevacizumab in Liver Disease | Peak Day 43 | 280 micrograms/mL |
| Arm I (TACE-BEV Arm) | Assess Pharmakokinetics of Bevacizumab in Liver Disease | Trough Day 43 | 84.7 micrograms/mL |
| Arm I (TACE-BEV Arm) | Assess Pharmakokinetics of Bevacizumab in Liver Disease | Peak Day 57 | 272 micrograms/mL |
| Arm I (TACE-BEV Arm) | Assess Pharmakokinetics of Bevacizumab in Liver Disease | Trough Day 57 | 97.7 micrograms/mL |
| Arm I (TACE-BEV Arm) | Assess Pharmakokinetics of Bevacizumab in Liver Disease | Peak Day 85 | 333 micrograms/mL |
| Arm I (TACE-BEV Arm) | Assess Pharmakokinetics of Bevacizumab in Liver Disease | Trough Day 85 | 119 micrograms/mL |
Secondary
Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment
Time frame: 16 weeks
Population: subjects that completed all 16 weeks.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (TACE-BEV Arm) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | proteinuria | 8 participants |
| Arm I (TACE-BEV Arm) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | fatigue | 9 participants |
| Arm I (TACE-BEV Arm) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | Constipation | 4 participants |
| Arm I (TACE-BEV Arm) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | hyperbilirubinemia | 8 participants |
| Arm I (TACE-BEV Arm) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | Anorexia | 5 participants |
| Arm I (TACE-BEV Arm) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | hypertension | 6 participants |
| Arm I (TACE-BEV Arm) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | Electrolyte abnormalities | 9 participants |
| Arm I (TACE-BEV Arm) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | hypoalbuminemia | 5 participants |
| Arm I (TACE-BEV Arm) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | Anemia | 3 participants |
| Arm I (TACE-BEV Arm) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | nausea and or vomiting | 6 participants |
| Arm I (TACE-BEV Arm) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | Elevated alkaline phosphatase | 4 participants |
| Arm I (TACE-BEV Arm) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | Bleeding | 8 participants |
| Arm I (TACE-BEV Arm) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | pyrexia | 8 participants |
| Arm I (TACE-BEV Arm) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | elevated transaminases | 15 participants |
| Arm I (TACE-BEV Arm) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | thrombocytopenia | 7 participants |
| Arm I (TACE-BEV Arm) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | pain | 11 participants |
| Arm II (TACE-O Arm ) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | thrombocytopenia | 10 participants |
| Arm II (TACE-O Arm ) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | pain | 13 participants |
| Arm II (TACE-O Arm ) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | Anemia | 6 participants |
| Arm II (TACE-O Arm ) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | Anorexia | 4 participants |
| Arm II (TACE-O Arm ) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | Bleeding | 1 participants |
| Arm II (TACE-O Arm ) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | Constipation | 3 participants |
| Arm II (TACE-O Arm ) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | Electrolyte abnormalities | 9 participants |
| Arm II (TACE-O Arm ) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | Elevated alkaline phosphatase | 3 participants |
| Arm II (TACE-O Arm ) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | elevated transaminases | 14 participants |
| Arm II (TACE-O Arm ) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | fatigue | 8 participants |
| Arm II (TACE-O Arm ) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | hyperbilirubinemia | 7 participants |
| Arm II (TACE-O Arm ) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | hypertension | 4 participants |
| Arm II (TACE-O Arm ) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | hypoalbuminemia | 7 participants |
| Arm II (TACE-O Arm ) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | nausea and or vomiting | 9 participants |
| Arm II (TACE-O Arm ) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | proteinuria | 1 participants |
| Arm II (TACE-O Arm ) | Assess the Toxicities of Bevacizumab in Patients With Liver Function Impairment | pyrexia | 7 participants |
Secondary
Measure (Vascular Endothelial Growth Factor)VEGF Before and After TACE With and Without Bevacizumab
Time frame: 21 days after TACE
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (TACE-BEV Arm) | Measure (Vascular Endothelial Growth Factor)VEGF Before and After TACE With and Without Bevacizumab | 1 hour | .053 fold change |
| Arm I (TACE-BEV Arm) | Measure (Vascular Endothelial Growth Factor)VEGF Before and After TACE With and Without Bevacizumab | 24 hours | .167 fold change |
| Arm I (TACE-BEV Arm) | Measure (Vascular Endothelial Growth Factor)VEGF Before and After TACE With and Without Bevacizumab | 48 hours | .161 fold change |
| Arm I (TACE-BEV Arm) | Measure (Vascular Endothelial Growth Factor)VEGF Before and After TACE With and Without Bevacizumab | 72 hours | .048 fold change |
| Arm I (TACE-BEV Arm) | Measure (Vascular Endothelial Growth Factor)VEGF Before and After TACE With and Without Bevacizumab | 360 hours | .039 fold change |
| Arm I (TACE-BEV Arm) | Measure (Vascular Endothelial Growth Factor)VEGF Before and After TACE With and Without Bevacizumab | 528 hours | .063 fold change |
| Arm I (TACE-BEV Arm) | Measure (Vascular Endothelial Growth Factor)VEGF Before and After TACE With and Without Bevacizumab | 696 hours | .06 fold change |
Secondary
Progression Free Survival
Progression free survival (PFS) at 16 weeks (end of the core phase).
Time frame: 16 weeks
Population: Arm I: Patients receive bevacizumab Arm II. Patients do not receive bevacizumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (TACE-BEV Arm) | Progression Free Survival | .79 probablility of pfs at 16 weeks |
| Arm II (TACE-O Arm ) | Progression Free Survival | .19 probablility of pfs at 16 weeks |