Adult Primary Hepatocellular Carcinoma, Localized Unresectable Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer
Conditions
Brief summary
This phase II trial is to see if bevacizumab works in treating patients who have unresectable nonmetastatic liver cancer that has not spread to the main portal vein. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or deliver cancer-killing substances to them.
Detailed description
OBJECTIVES: I. Determine the efficacy of bevacizumab, in terms of progression-free survival and disease stability and response, in patients with unresectable nonmetastatic hepatocellular cancer (HCC) without main portal vein invasion. II. Determine the safety of this drug in these patients. III. Assess tumor vascular perfusion kinetics, by dynamic gadolinium-enhanced MRI, in patients before and after treatment with this regimen. IV. Determine the effect of vascular endothelial growth factor (VEGF)-inhibition by this drug on circulating levels of VEGF and related cytokines that also contribute to HCC pathogenesis (including bFGF, TGF-alpha, and IGF-II) and on potential alterations of these levels on prognostic variables in these patients. V. Determine the effect of VEGF-inhibition by this drug on hepatic function and hepatitis viral activity in cirrhosis in these patients. OUTLINE: This is a multicenter, pilot study. Patients receive bevacizumab IV over 30-90 minutes on day 1. Treatment continues every 2 weeks in the absence of disease progression or unacceptable toxicity. PROJECTED ACCRUAL: A total of 18-46 patients will be accrued for this study.
Interventions
BIOLOGICALbevacizumab
Given orally
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed hepatocellular carcinoma * Confirmed by needle aspirate, biopsy, or prior surgical resection specimen * Clinically confirmed hepatocellular carcinoma defined as follows: * Cirrhosis or chronic hepatitis B or C virus infection, with 1 or more hypervascular liver masses more than 2 cm * Alpha-fetoprotein (AFP) greater than 400 ng/mL OR greater than 3 times normal and doubling in value during the past 3 months * Deemed unresectable * Prior surgical resection allowed * Recurrence after hepatic resection or other procedure allowed * Tumor that extends into branches of the portal or hepatic veins allowed * No tumor invading the main portal vein (portal trunk) or inferior vena cava * No tumor occupying more than 50% of the liver volume * Enlargement/involvement of regional lymph nodes allowed * At least 1 unidimensionally measurable lesion at least 20 mm * No poorly defined lesions * No vague hypervascular patches * Child-Pugh class A or compensated Child-Pugh class B liver dysfunction * No Child-Pugh class C or uncompensated class B indicated by active encephalopathy, persistent ascites, or prothrombin time greater than 1.5 times normal * Prior ascites allowed if manageable with diuretics alone * No repeated paracentesis (more than 1 per month) * No extrahepatic metastasis * No documented brain metastases * No history or clinical evidence of CNS disease (e.g., primary brain tumor, seizures uncontrolled with standard medical therapy, or history of stroke) * Performance status - ECOG 0-2 * Absolute neutrophil count greater than 1,500/mm\^3 * Hemoglobin at least 8 g/dL * Platelet count at least 75,000/mm\^3 * No prior serious bleeding event (unrelated to liver disease) * No bleeding diathesis * No coagulopathy * Bilirubin no greater than 3 mg/dL * Transaminases less than 5 times upper limit of normal (ULN) * Albumin at least 2.5 mg/dL * PTT less than 4 seconds above ULN * INR less than 1.5 (for patients receiving warfarin) * Creatinine less than 1.5 g/dL * Urine protein less than 500 mg/24hrs\*
Exclusion criteria
* No thromboembolic event within the past 12 months * No clinically significant cardiovascular disease * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No active infection requiring parenteral antibiotics * No serious non-healing wound/ulcer or bone fracture * No variceal bleeding within the past 6 months * No malignancy within the past 5 years except localized nonmelanoma skin cancer * No ongoing psychiatric or social situation that would preclude study compliance * No known hypersensitivity to Chinese hamster ovary cell products * No known hypersensitivity to other recombinant human antibodies * No more than 1 prior biologic therapy * No concurrent interferon * No concurrent interleukin-2 * No more than 1 prior antineoplastic chemotherapy * At least 4 weeks since prior invasive surgery, including open biopsy * At least 2 weeks since prior needle biopsy (core or fine-needle aspirate) * No concurrent hepatic transplant * At least 4 weeks since prior anticancer therapy * No concurrent platelet-stimulating factors (e.g., oprelvekin) * No concurrent full-dose anticoagulants or thrombolytic agents (except as required to maintain patency of pre-existing, permanent indwelling IV catheters) * No chronic daily antiplatelet drugs (e.g., aspirin doses of 325 mg/day or higher or non-steroidal anti-inflammatory drugs)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | At 6 months | — |
| Disease Response | MRI is required at weeks 8, 16 and then every 12 weeks until disease progression | MRI scan is required at weeks 8, 16 and then every 12 weeks until disease progression. Per Response Evaluation Criteria in Solid Tumors (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR |
| Mean Arterial Enhancement, Per Lesion, as Determined by Dynamic Gadolinium-enhanced Magnetic Resonance Imaging (MRI), Before and Following Bevacizumab Therapy. | Baseline and 8 weeks after bevacizumab therapy | — |
| Assessment on Circulating Levels of VEGF Which Also Contribute to HCC Pathogenesis and on Potential Alterations of These Levels in the Setting of VEGF-inhibition | During treatment | — |
| To Collect Information on Hepatic Function and Hepatitis Viral Activity in Cirrhosis and Upon Potential Alterations in the Setting of VEGF-inhibition | During and after treatment | — |
Other
| Measure | Time frame |
|---|---|
| Disease Stability | At 6 months |
Countries
United States
Participant flow
Recruitment details
A total of 46 patients were enrolled between February 2003 and September 2006
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Bevacizumab) Patients receive bevacizumab IV over 30-90 minutes on day 1. Treatment continues every 2 weeks in the absence of disease progression or unacceptable toxicity.
bevacizumab: Given orally | 46 |
| Total | 46 |
Baseline characteristics
| Characteristic | Treatment (Bevacizumab) |
|---|---|
| Age, Continuous | 58 years |
| Race/Ethnicity, Customized Asian | 14 participants |
| Race/Ethnicity, Customized Black | 2 participants |
| Race/Ethnicity, Customized Hispanic | 5 participants |
| Race/Ethnicity, Customized White | 25 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 41 / 46 |
| serious Total, serious adverse events | 22 / 46 |
Outcome results
Primary
Assessment on Circulating Levels of VEGF Which Also Contribute to HCC Pathogenesis and on Potential Alterations of These Levels in the Setting of VEGF-inhibition
Time frame: During treatment
Population: Six of eight patients were analyzed after 8 weeks of bevacizumab therapy
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Bevacizumab) | Assessment on Circulating Levels of VEGF Which Also Contribute to HCC Pathogenesis and on Potential Alterations of These Levels in the Setting of VEGF-inhibition | 249 pg/mL | Standard Deviation 175 |
Primary
Disease Response
MRI scan is required at weeks 8, 16 and then every 12 weeks until disease progression. Per Response Evaluation Criteria in Solid Tumors (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time frame: MRI is required at weeks 8, 16 and then every 12 weeks until disease progression
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Bevacizumab) | Disease Response | 6 participants |
Primary
Mean Arterial Enhancement, Per Lesion, as Determined by Dynamic Gadolinium-enhanced Magnetic Resonance Imaging (MRI), Before and Following Bevacizumab Therapy.
Time frame: Baseline and 8 weeks after bevacizumab therapy
Population: Eight consecutive patients enrolled at one site were evaluated before and at 8 weeks after bevacizumab therapy with DCE-MRI.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Bevacizumab) | Mean Arterial Enhancement, Per Lesion, as Determined by Dynamic Gadolinium-enhanced Magnetic Resonance Imaging (MRI), Before and Following Bevacizumab Therapy. | 37.3 relative MR units | Standard Deviation 18.4 |
| Treatment (Bevacizumab): 8 Weeks | Mean Arterial Enhancement, Per Lesion, as Determined by Dynamic Gadolinium-enhanced Magnetic Resonance Imaging (MRI), Before and Following Bevacizumab Therapy. | 18.4 relative MR units | Standard Deviation 12.4 |
Primary
Progression-free Survival
Time frame: At 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Bevacizumab) | Progression-free Survival | 65 percentage of participants |
Primary
To Collect Information on Hepatic Function and Hepatitis Viral Activity in Cirrhosis and Upon Potential Alterations in the Setting of VEGF-inhibition
Time frame: During and after treatment
Population: No data was collected by the principal investigator for this outcome
Other Pre-specified
Disease Stability
Time frame: At 6 months