Liver Cancer
Conditions
Keywords
adult primary hepatocellular carcinoma, localized unresectable adult primary liver cancer, advanced adult primary liver cancer, recurrent adult primary liver cancer, adult primary cholangiocellular carcinoma
Brief summary
RATIONALE: Drugs used in chemotherapy, such as floxuridine and dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving chemotherapy directly into the arteries around the tumor together with bevacizumab may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving floxuridine and dexamethasone as a hepatic arterial infusion together with bevacizumab works in treating patients with unresectable primary liver cancer.
Detailed description
OBJECTIVES: Primary * Determine the median time to progression in patients with unresectable primary hepatic malignancy treated with hepatic arterial infusion comprising floxuridine and dexamethasone in combination with systemic bevacizumab. Secondary * Determine the utility of dynamic contrast-enhanced MRI (DCE-MRI) for assessing changes in tumor perfusion before and during treatment. * Correlate DCE-MRI findings with radiographic tumor response. Tertiary * Correlate the expression patterns of vascular endothelial growth factor (VEGF) receptor (VEGFR)-1, VEGFR-2, and VEGFR-3 and their cognate ligands (including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placenta growth factor \[PlGF\]) with disease progression and survival after therapy. * Assess the pro-angiogenic activity of peripheral blood before and during treatment. * Assess tumors for immunohistochemical markers of hypoxia (e.g., hypoxia-inducible factor \[HIF-1α\], carbonic anhydrase IX \[CA IX\], and glucose transporters \[Glut-1 and Glut-3\]) for correlation with initial and treatment-related changes in perfusion and permeability, as determined by DCE-MRI. OUTLINE: This is an open-label, nonrandomized study. Patients undergo placement of the hepatic arterial infusion (HAI) pump and a cholecystectomy. Approximately 2 weeks later, patients receive floxuridine and dexamethasone by HAI continuously on days 1-14 and bevacizumab IV over 30-90 minutes on day 15 of course 1 and on days 1 and 15 of all subsequent courses. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo dynamic contrast-enhanced MRI (DCE-MRI) on days 1 and 15 of course 1 and then every 8 weeks thereafter. Tumor and nontumor tissue is collected at the time of the HAI pump placement. Tissue is examined for the expression of vascular endothelial growth factor (VEGF)-A, -B, -C, and -D, placenta growth factor (PlGF), and VEGF receptor (VEGFR)-1, -2, and -3 by immunohistochemistry. Peripheral blood is collected at baseline and on day 1 of each course. Plasma levels of VEGF-A, -B, -C, and -D are measured by immunoenzyme techniques. Blood is also examined by flow cytometry and immunological methods and by protein extraction and analysis of VEGF and VEGFR expression (by western blot). Immunohistochemical markers of hypoxia in tissue, including hypoxia-inducible factor (HIF-1α), carbonic anhydrase IX (CA IX), glucose transporters (Glut-1 and Glut-3), and Ki-67 are assessed. After completion of study treatment, patients are followed periodically. PROJECTED ACCRUAL: A total of 55 patients will be accrued for this study.
Interventions
BIOLOGICALbevacizumab
DRUGdexamethasone
DRUGfloxuridine
GENETICprotein expression analysis
OTHERflow cytometry
OTHERimmunoenzyme technique
OTHERimmunohistochemistry staining method
OTHERimmunologic technique
OTHERlaboratory biomarker analysis
PROCEDUREdynamic contrast-enhanced magnetic resonance imaging
Sponsors
National Cancer Institute (NCI)
Memorial Sloan Kettering Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) * Peripheral, cholangiolar, or cholangiocellular types * Mixed HCC/ICC disease allowed * Unresectable disease * Less than 70% liver involvement * Radiographically bidimensionally measurable disease, defined as lesion ≥ 2 cm in the greatest diameter * May have failed prior systemic chemotherapy or ablative therapy * No radiographic evidence of esophageal varices * No history of variceal hemorrhage * No occlusion of the main portal vein or the right and left portal branches * No clinical ascites * Patients ineligible for first-line MSKCC protocols for HCC are eligible for this study provided there is no clinical or radiographic evidence of extrahepatic disease * No metastatic disease, including CNS metastases PATIENT CHARACTERISTICS: * Life expectancy ≥ 12 weeks * Karnofsky performance status 60-100% * Considered a candidate for general anesthesia and hepatic artery pump placement * Platelet count \> 100,000/mm³ * Albumin \> 2.5 g/dL * Bilirubin \< 1.8 mg/dL * WBC \> 3,500/mm³ * PTT \< 1.5 times upper limit of normal * INR \< 1.5 OR in-range INR (usually 2.0-3.0) for patients on a stable dose of therapeutic warfarin * Urine protein \< 1+ by dipstick or urine analysis OR urine protein:creatinine ratio \< 1.0 * If proteinuria ≥ 2+ at baseline, patient must have \< 1 g protein/24-hour collection * No concurrent disease or illness that would preclude study participation, including any of the following: * Hepatic encephalopathy * Sclerosing cholangitis * Gilbert's disease * Active infection * No known CNS disease * No history of allergic reactions attributed to compounds of similar chemical or biologic composition to bevacizumab * No psychiatric illness or social situation that would preclude study compliance * No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months * No serious or nonhealing active wound, ulcer, or bone fracture * No bleeding diathesis or coagulopathy * No clinically significant cardiovascular disease, including any of the following: * Uncontrolled hypertension, defined as systolic blood pressure (BP) \> 150 mm Hg or diastolic BP \> 100 mm Hg on antihypertensive medications * New York Heart Association class II-IV congestive heart failure * Vascular disease (e.g., aortic aneurysm, aortic dissection) * Myocardial infarction within the past 6 months * Symptomatic peripheral vascular disease * Unstable angina within the past 6 months * History of hypertensive crisis * Transient ischemic attack * Stroke * No other concurrent malignancy except localized basal cell or squamous cell skin cancer * Chronic hepatitis and/or cirrhosis allowed provided it is Child-Pugh class A disease * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: * See Disease Characteristics * More than 4 weeks since prior and no other concurrent experimental therapy except on a Genentech-sponsored bevacizumab cancer study * More than 4 weeks since prior major surgical procedure or open biopsy * More than 1 week since prior minor surgical procedure (e.g., core biopsy), excluding placement of a vascular access device * No prior external-beam radiation therapy to the liver * No prior floxuridine * No chronic daily treatment with nonsteroidal anti-inflammatory medications known to inhibit platelet function * No chronic daily treatment with aspirin (\> 325 mg/day) * No concurrent or recent use of a thrombolytic agent * No concurrent major surgery
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Overall Survival | Up to 36 months | Overall median survival from time of initiation of HAI + Bev |
| Median Hepatic Progression Free Survival | Up to 36 months | Median Hepatic Progression Free Survival. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
| Median Progression Free Survival | Up to 36 months | Median Progression Free Survival. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
| Antitumor Efficacy (Complete and Partial Response, Stable and Progressive Disease) | Up to 36 months | Antitumor efficacy (complete and partial response, stable and progressive disease). Per Response Evaluation Criteria In Solid Tumors Criteria (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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Evaluated for Toxicity as Measured by NCI Common Toxicity Criteria | 2 years | Toxicity as measured by NCI Common Toxicity Criteria |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| UNRESECTABLE PRIMARY HEPATIC MALIGNANCY All patients enrolled in the study will receive HAI FUDR (0.16 mg/kg X pump volume / pump flow rate), Dexamethasone (1 mg/m2/day) and IV Bevacizumab at 5mg/kg. Chemotherapy with HAI FUDR/Dex will commence no sooner than 14 days post surgical placement of HAI pump; patients will receive their first treatment with Bevacizumab no sooner than 28 days post surgical placement of HAI pump.
bevacizumab
dexamethasone
floxuridine
protein expression analysis
flow cytometry
immunoenzyme technique
immunohistochemistry staining method
immunologic technique
laboratory biomarker analysis
dynamic contrast-enhanced magnetic resonance imaging | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Death | 2 |
| Overall Study | Lack of Efficacy | 10 |
| Overall Study | Physician Decision | 6 |
Baseline characteristics
| Characteristic | UNRESECTABLE PRIMARY HEPATIC MALIGNANCY |
|---|---|
| Age, Continuous | 61 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 21 Participants |
| Region of Enrollment United States | 22 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 21 / 22 |
| other Total, other adverse events | 17 / 22 |
| serious Total, serious adverse events | 12 / 22 |
Outcome results
Primary
Antitumor Efficacy (Complete and Partial Response, Stable and Progressive Disease)
Antitumor efficacy (complete and partial response, stable and progressive disease). Per Response Evaluation Criteria In Solid Tumors Criteria (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: Up to 36 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| UNRESECTABLE PRIMARY HEPATIC MALIGNANCY | Antitumor Efficacy (Complete and Partial Response, Stable and Progressive Disease) | Partial Response | 7 Participants |
| UNRESECTABLE PRIMARY HEPATIC MALIGNANCY | Antitumor Efficacy (Complete and Partial Response, Stable and Progressive Disease) | Stable Disease | 15 Participants |
Primary
Median Hepatic Progression Free Survival
Median Hepatic Progression Free Survival. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: Up to 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| UNRESECTABLE PRIMARY HEPATIC MALIGNANCY | Median Hepatic Progression Free Survival | 11.28 months |
Primary
Median Overall Survival
Overall median survival from time of initiation of HAI + Bev
Time frame: Up to 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| UNRESECTABLE PRIMARY HEPATIC MALIGNANCY | Median Overall Survival | 31.1 months |
Primary
Median Progression Free Survival
Median Progression Free Survival. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: Up to 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| UNRESECTABLE PRIMARY HEPATIC MALIGNANCY | Median Progression Free Survival | 8.45 months |
Secondary
Number of Participants Evaluated for Toxicity as Measured by NCI Common Toxicity Criteria
Toxicity as measured by NCI Common Toxicity Criteria
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| UNRESECTABLE PRIMARY HEPATIC MALIGNANCY | Number of Participants Evaluated for Toxicity as Measured by NCI Common Toxicity Criteria | 22 Participants |